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Pathological consequences of DNA damage in the kidney

Abstract

DNA lesions that evade repair can lead to mutations that drive the development of cancer, and cellular responses to DNA damage can trigger senescence and cell death, which are associated with ageing. In the kidney, DNA damage has been implicated in both acute and chronic kidney injury, and in renal cell carcinoma. The susceptibility of the kidney to chemotherapeutic agents that damage DNA is well established, but an unexpected link between kidney ciliopathies and the DNA damage response has also been reported. In addition, human genetic deficiencies in DNA repair have highlighted DNA crosslinks, DNA breaks and transcription-blocking damage as lesions that are particularly toxic to the kidney. Genetic tools in mice, as well as advances in kidney organoid and single-cell RNA sequencing technologies, have provided important insights into how specific kidney cell types respond to DNA damage. The emerging view is that in the kidney, DNA damage affects the local microenvironment by triggering a damage response and cell proliferation to replenish injured cells, as well as inducing systemic responses aimed at reducing exposure to genotoxic stress. The pathological consequences of DNA damage are therefore key to the nephrotoxicity of DNA-damaging agents and the kidney phenotypes observed in human DNA repair-deficiency disorders.

Key points

  • DNA damage has an important role in the functional decline of tissues associated with ageing, and DNA damage that evades repair can also lead to mutations that drive the development of cancer.

  • The kidney is exquisitely sensitive to chemotherapeutic and environmental agents that damage DNA, leading to both acute and chronic kidney injury.

  • An unexpected and currently incompletely understood link between kidney ciliopathies and the DNA damage response has emerged.

  • Genetic DNA repair defects in humans have highlighted DNA crosslinks, DNA breaks and transcription-blocking damage as particularly toxic lesions to the kidney.

  • Advances in mouse genetic tools, kidney organoids and single-cell RNA sequencing have been instrumental in clarifying how specific kidney cell types respond to DNA damage.

  • DNA damage in kidney cells adversely affects the local microenvironment and elicits systemic responses through signalling pathways that are engaged to potentially reduce tissue exposure to genotoxic stress.

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Fig. 1: An overview of DNA damage repair pathways.
Fig. 2: The DNA repair toolkit.
Fig. 3: DNA damage responses in the kidney.
Fig. 4: Kidney ciliopathies with links to DNA damage.
Fig. 5: Checkpoint activation in the injured kidney.

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References

  1. Jackson, S. P. & Bartek, J. The DNA-damage response in human biology and disease. Nature 461, 1071–1078 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Mitchell, J. R., Hoeijmakers, J. H. & Niedernhofer, L. J. Divide and conquer: nucleotide excision repair battles cancer and ageing. Curr. Opin. Cell Biol. 15, 232–240 (2003).

    Article  CAS  PubMed  Google Scholar 

  3. Hoeijmakers, J. H. Genome maintenance mechanisms for preventing cancer. Nature 411, 366–374 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Negrini, S., Gorgoulis, V. G. & Halazonetis, T. D. Genomic instability — an evolving hallmark of cancer. Nat. Rev. Mol. Cell Biol. 11, 220–228 (2010).

    Article  CAS  PubMed  Google Scholar 

  5. Polo, S. E. & Jackson, S. P. Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications. Genes Dev. 25, 409–433 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bekker-Jensen, S. & Mailand, N. Assembly and function of DNA double-strand break repair foci in mammalian cells. DNA Repair. 9, 1219–1228 (2011).

    Article  Google Scholar 

  7. Ciccia, A. & Elledge, S. J. The DNA damage response: making it safe to play with knives. Mol. Cell 40, 179–204 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Balzer, M. S., Rohacs, T. & Susztak, K. How many cell types are in the kidney and what do they do? Annu. Rev. Physiol. 84, 507–531 (2022).

    Article  PubMed  Google Scholar 

  9. Hayashi, K. et al. Association of glomerular DNA damage and DNA methylation with one-year eGFR decline in IgA nephropathy. Sci. Rep. 10, 237 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yamashita, N. et al. Cumulative DNA damage by repeated low-dose cisplatin injection promotes the transition of acute to chronic kidney injury in mice. Sci. Rep. 11, 20920 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gupta, N. et al. Modeling injury and repair in kidney organoids reveals that homologous recombination governs tubular intrinsic repair. Sci. Transl. Med. 14, eabj4772 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ferenbach, D. A. & Bonventre, J. V. Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD. Nat. Rev. Nephrol. 11, 264–276 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yang, L., Besschetnova, T. Y., Brooks, C. R., Shah, J. V. & Bonventre, J. V. Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat. Med. 16, 535–543 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Giglia-Mari, G., Zotter, A. & Vermeulen, W. DNA damage response. Cold Spring Harb. Perspect. Biol. 3, a000745 (2010).

    Google Scholar 

  15. de Laat, W. L., Jaspers, N. G. & Hoeijmakers, J. H. Molecular mechanism of nucleotide excision repair. Genes Dev. 13, 768–785 (1999).

    Article  PubMed  Google Scholar 

  16. Sugasawa, K. et al. Xeroderma pigmentosum group C protein complex is the initiator of global genome nucleotide excision repair. Mol. Cell 2, 223–232 (1998).

    Article  CAS  PubMed  Google Scholar 

  17. Volker, M. et al. Sequential assembly of the nucleotide excision repair factors in vivo. Mol. Cell 8, 213–224 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. van der Weegen, Y. et al. The cooperative action of CSB, CSA, and UVSSA target TFIIH to DNA damage-stalled RNA polymerase II. Nat. Commun. 11, 2104 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Nakazawa, Y. et al. Ubiquitination of DNA damage-stalled RNAPII promotes transcription-coupled repair. Cell 180, 1228–1244.e1224 (2020).

    Article  CAS  PubMed  Google Scholar 

  20. Marteijn, J. A., Lans, H., Vermeulen, W. & Hoeijmakers, J. H. Understanding nucleotide excision repair and its roles in cancer and ageing. Nat. Rev. Mol. Cell Biol. 15, 465–481 (2014).

    Article  CAS  PubMed  Google Scholar 

  21. Wakasugi, M. & Sancar, A. Assembly, subunit composition, and footprint of human DNA repair excision nuclease. Proc. Natl Acad. Sci. USA 95, 6669–6674 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Riedl, T., Hanaoka, F. & Egly, J. M. The comings and goings of nucleotide excision repair factors on damaged DNA. EMBO J. 22, 5293–5303 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kokic, G. et al. Structural basis of TFIIH activation for nucleotide excision repair. Nat. Commun. 10, 2885 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Tsodikov, O. V. et al. Structural basis for the recruitment of ERCC1-XPF to nucleotide excision repair complexes by XPA. EMBO J. 26, 4768–4776 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Li, L., Peterson, C. A., Lu, X. & Legerski, R. J. Mutations in XPA that prevent association with ERCC1 are defective in nucleotide excision repair. Mol. Cell Biol. 15, 1993–1998 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Staresincic, L. et al. Coordination of dual incision and repair synthesis in human nucleotide excision repair. EMBO J. 28, 1111–1120 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Matsunaga, T., Mu, D., Park, C. H., Reardon, J. T. & Sancar, A. Human DNA repair excision nuclease. Analysis of the roles of the subunits involved in dual incisions by using anti-XPG and anti-ERCC1 antibodies. J. Biol. Chem. 270, 20862–20869 (1995).

    Article  CAS  PubMed  Google Scholar 

  28. O’Donovan, A., Davies, A. A., Moggs, J. G., West, S. C. & Wood, R. D. XPG endonuclease makes the 3’ incision in human DNA nucleotide excision repair. Nature 371, 432–435 (1994).

    Article  PubMed  Google Scholar 

  29. Friedberg, E. C., Wagner, R. & Radman, M. Specialized DNA polymerases, cellular survival, and the genesis of mutations. Science 296, 1627–1630 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Lehmann, A. R. et al. Translesion synthesis: Y-family polymerases and the polymerase switch. DNA Repair. 6, 891–899 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Masutani, C. et al. The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase eta. Nature 399, 700–704 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. Sy, S. M., Huen, M. S. & Chen, J. PALB2 is an integral component of the BRCA complex required for homologous recombination repair. Proc. Natl Acad. Sci. USA 106, 7155–7160 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhang, F., Fan, Q., Ren, K. & Andreassen, P. R. PALB2 functionally connects the breast cancer susceptibility proteins BRCA1 and BRCA2. Mol. Cancer Res. 7, 1110–1118 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhang, F. et al. PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Curr. Biol. 19, 524–529 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wyman, C. & Kanaar, R. DNA double-strand break repair: all’s well that ends well. Annu. Rev. Genet. 40, 363–383 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. McKinnon, P. J. & Caldecott, K. W. DNA strand break repair and human genetic disease. Annu. Rev. Genomics Hum. Genet. 8, 37–55 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Helfricht, A. et al. Loss of ZBTB24 impairs nonhomologous end-joining and class-switch recombination in patients with ICF syndrome. J. Exp. Med. 217, e20191688 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Walden, H. & Deans, A. J. The Fanconi anemia DNA repair pathway: structural and functional insights into a complex disorder. Annu. Rev. Biophys. 43, 257–278 (2014).

    Article  CAS  PubMed  Google Scholar 

  39. Wood, R. D. Mammalian nucleotide excision repair proteins and interstrand crosslink repair. Env. Mol. Mutagen. 51, 520–526 (2010).

    CAS  Google Scholar 

  40. Klein Douwel, D. et al. XPF-ERCC1 acts in unhooking DNA interstrand crosslinks in cooperation with FANCD2 and FANCP/SLX4. Mol. Cell 54, 460–471 (2014).

    Article  CAS  PubMed  Google Scholar 

  41. Abdullah, U. B. et al. RPA activates the XPF-ERCC1 endonuclease to initiate processing of DNA interstrand crosslinks. EMBO J. 36, 2047–2060 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kuraoka, I. et al. Repair of an interstrand DNA cross-link initiated by ERCC1-XPF repair/recombination nuclease. J. Biol. Chem. 275, 26632–26636 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. Auerbach, A. D. Fanconi anemia and its diagnosis. Mutat. Res. 668, 4–10 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kashiyama, K. et al. Malfunction of nuclease ERCC1-XPF results in diverse clinical manifestations and causes Cockayne syndrome, xeroderma pigmentosum, and Fanconi anemia. Am. J. Hum. Genet. 92, 807–819 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bogliolo, M. et al. Mutations in ERCC4, encoding the DNA-repair endonuclease XPF, cause Fanconi anemia. Am. J. Hum. Genet. 92, 800–806 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ceccaldi, R., Sarangi, P. & D’Andrea, A. D. The Fanconi anaemia pathway: new players and new functions. Nat. Rev. Mol. Cell Biol. 17, 337–349 (2016).

    Article  CAS  PubMed  Google Scholar 

  47. Warmerdam, D. O. & Kanaar, R. Dealing with DNA damage: relationships between checkpoint and repair pathways. Mutat. Res. 704, 2–11 (2010).

    Article  CAS  PubMed  Google Scholar 

  48. Huen, M. S. & Chen, J. Assembly of checkpoint and repair machineries at DNA damage sites. Trends Biochem. Sci. 35, 101–108 (2010).

    Article  CAS  PubMed  Google Scholar 

  49. Lee, J. H. & Paull, T. T. ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science 308, 551–554 (2005).

    Article  CAS  PubMed  Google Scholar 

  50. Shiotani, B. & Zou, L. Single-stranded DNA orchestrates an ATM-to-ATR switch at DNA breaks. Mol. Cell 33, 547–558 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zou, L. & Elledge, S. J. Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science 300, 1542–1548 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Vrouwe, M. G., Pines, A., Overmeer, R. M., Hanada, K. & Mullenders, L. H. UV-induced photolesions elicit ATR-kinase-dependent signaling in non-cycling cells through nucleotide excision repair-dependent and -independent pathways. J. Cell Sci. 124, 435–446 (2011).

    Article  CAS  PubMed  Google Scholar 

  53. Zhang, X. P., Liu, F. & Wang, W. Two-phase dynamics of p53 in the DNA damage response. Proc. Natl Acad. Sci. USA 108, 8990–8995 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Han, J., Xian, Z., Zhang, Y., Liu, J. & Liang, A. Systematic overview of aristolochic acids: nephrotoxicity, carcinogenicity, and underlying mechanisms. Front. Pharmacol. 10, 648 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Arlt, V. M., Stiborova, M. & Schmeiser, H. H. Aristolochic acid as a probable human cancer hazard in herbal remedies: a review. Mutagenesis 17, 265–277 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Grollman, A. P. et al. Aristolochic acid and the etiology of endemic (Balkan) nephropathy. Proc. Natl Acad. Sci. USA 104, 12129–12134 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Schmeiser, H. H. et al. Exceptionally long-term persistence of DNA adducts formed by carcinogenic aristolochic acid I in renal tissue from patients with aristolochic acid nephropathy. Int. J. Cancer 135, 502–507 (2014).

    Article  CAS  PubMed  Google Scholar 

  58. Sidorenko, V. S. et al. Lack of recognition by global-genome nucleotide excision repair accounts for the high mutagenicity and persistence of aristolactam-DNA adducts. Nucleic Acids Res. 40, 2494–2505 (2012).

    Article  CAS  PubMed  Google Scholar 

  59. Moriya, M. et al. TP53 Mutational signature for aristolochic acid: an environmental carcinogen. Int. J. Cancer 129, 1532–1536 (2011).

    Article  CAS  PubMed  Google Scholar 

  60. Alexandrov, L. B. et al. The repertoire of mutational signatures in human cancer. Nature 578, 94–101 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Navarro Garrido, A. et al. Aristolochic acid-induced nephropathy is attenuated in mice lacking the neutral amino acid transporter B(0)AT1 (Slc6a19). Am. J. Physiol. Renal Physiol. 323, F455–F467 (2022).

    Article  PubMed  Google Scholar 

  62. Dickman, K. G., Sweet, D. H., Bonala, R., Ray, T. & Wu, A. Physiological and molecular characterization of aristolochic acid transport by the kidney. J. Pharmacol. Exp. Ther. 338, 588–597 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Manohar, S. & Leung, N. Cisplatin nephrotoxicity: a review of the literature. J. Nephrol. 31, 15–25 (2018).

    Article  CAS  PubMed  Google Scholar 

  64. Zhu, S., Pabla, N., Tang, C., He, L. & Dong, Z. DNA damage response in cisplatin-induced nephrotoxicity. Arch. Toxicol. 89, 2197–2205 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ludwig, T., Riethmuller, C., Gekle, M., Schwerdt, G. & Oberleithner, H. Nephrotoxicity of platinum complexes is related to basolateral organic cation transport. Kidney Int. 66, 196–202 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. Ciarimboli, G. et al. Cisplatin nephrotoxicity is critically mediated via the human organic cation transporter 2. Am. J. Pathol. 167, 1477–1484 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kusaba, T., Lalli, M., Kramann, R., Kobayashi, A. & Humphreys, B. D. Differentiated kidney epithelial cells repair injured proximal tubule. Proc. Natl Acad. Sci. USA 111, 1527–1532 (2014).

    Article  CAS  PubMed  Google Scholar 

  68. Yu, S. M. & Bonventre, J. V. Acute kidney injury and maladaptive tubular repair leading to renal fibrosis. Curr. Opin. Nephrol. Hypertens. 29, 310–318 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Kishi, S. et al. Proximal tubule ATR regulates DNA repair to prevent maladaptive renal injury responses. J. Clin. Invest. 129, 4797–4816 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Adamo, A. et al. Preventing nonhomologous end joining suppresses DNA repair defects of Fanconi anemia. Mol. Cell 39, 25–35 (2010).

    Article  CAS  PubMed  Google Scholar 

  71. Pace, P. et al. Ku70 corrupts DNA repair in the absence of the Fanconi anemia pathway. Science 329, 219–223 (2010).

    Article  CAS  PubMed  Google Scholar 

  72. Gherman, A., Davis, E. E. & Katsanis, N. The ciliary proteome database: an integrated community resource for the genetic and functional dissection of cilia. Nat. Genet. 38, 961–962 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. Hildebrandt, F., Attanasio, M. & Otto, E. Nephronophthisis: disease mechanisms of a ciliopathy. J. Am. Soc. Nephrol. 20, 23–35 (2009).

    Article  CAS  PubMed  Google Scholar 

  74. McConnachie, D. J., Stow, J. L. & Mallett, A. J. Ciliopathies and the kidney: a review. Am. J. Kidney Dis. 77, 410–419 (2021).

    Article  CAS  PubMed  Google Scholar 

  75. Devane, J. et al. Progressive liver, kidney, and heart degeneration in children and adults affected by TULP3 mutations. Am. J. Hum. Genet. 109, 928–943 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Chaki, M. et al. Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling. Cell 150, 533–548 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Choi, H. J. et al. NEK8 links the ATR-regulated replication stress response and S phase CDK activity to renal ciliopathies. Mol. Cell 51, 423–439 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Airik, R. et al. Renal-retinal ciliopathy gene Sdccag8 regulates DNA damage response signaling. J. Am. Soc. Nephrol. 25, 2573–2583 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Jain, M. et al. Inactivation of apoptosis antagonizing transcription factor in tubular epithelial cells induces accumulation of DNA damage and nephronophthisis. Kidney Int. 95, 846–858 (2019).

    Article  CAS  PubMed  Google Scholar 

  80. Sivasubramaniam, S., Sun, X., Pan, Y. R., Wang, S. & Lee, E. Y. Cep164 is a mediator protein required for the maintenance of genomic stability through modulation of MDC1, RPA, and CHK1. Genes Dev. 22, 587–600 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Slaats, G. G. et al. Nephronophthisis-associated CEP164 regulates cell cycle progression, apoptosis and epithelial-to-mesenchymal transition. PLoS Genet. 10, e1004594 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Casoni, F. et al. Zfp423/ZNF423 regulates cell cycle progression, the mode of cell division and the DNA-damage response in Purkinje neuron progenitors. Development 144, 3686–3697 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Bruno, T. et al. Che-1 phosphorylation by ATM/ATR and Chk2 kinases activates p53 transcription and the G2/M checkpoint. Cancer Cell 10, 473–486 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Hopker, K. et al. AATF/Che-1 acts as a phosphorylation-dependent molecular modulator to repress p53-driven apoptosis. EMBO J. 31, 3961–3975 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Slaats, G. G. et al. DNA replication stress underlies renal phenotypes in CEP290-associated Joubert syndrome. J. Clin. Invest. 125, 3657–3666 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Legue, E. & Liem, K. F. Jr Tulp3 Is a ciliary trafficking gene that regulates polycystic kidney disease. Curr. Biol. 29, 803–812 e805 (2019).

    Article  CAS  PubMed  Google Scholar 

  87. Hwang, S. H. et al. Tulp3 Regulates renal cystogenesis by trafficking of cystoproteins to cilia. Curr. Biol. 29, 790–802 e795 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Chen, T. Y. et al. Genotoxic stress-activated DNA-PK-p53 cascade and autophagy cooperatively induce ciliogenesis to maintain the DNA damage response. Cell Death Differ. 28, 1865–1879 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Bukanov, N. O., Smith, L. A., Klinger, K. W., Ledbetter, S. R. & Ibraghimov-Beskrovnaya, O. Long-lasting arrest of murine polycystic kidney disease with CDK inhibitor roscovitine. Nature 444, 949–952 (2006).

    Article  CAS  PubMed  Google Scholar 

  90. Reid, S. et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat. Genet. 39, 162–164 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Scott, R. H., Stiller, C. A., Walker, L. & Rahman, N. Syndromes and constitutional chromosomal abnormalities associated with Wilms tumour. J. Med. Genet. 43, 705–715 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Reid, S. et al. Biallelic BRCA2 mutations are associated with multiple malignancies in childhood including familial Wilms tumour. J. Med. Genet. 42, 147–151 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Svojgr, K. et al. Fanconi anemia with biallelic FANCD1/BRCA2 mutations — case report of a family with three affected children. Eur. J. Med. Genet. 59, 152–157 (2016).

    Article  PubMed  Google Scholar 

  94. Gadd, S. et al. A Children’s Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor. Nat. Genet. 49, 1487–1494 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Diets, I. J. et al. TRIM28 haploinsufficiency predisposes to Wilms tumor. Int. J. Cancer 145, 941–951 (2019).

    Article  CAS  PubMed  Google Scholar 

  96. Pietrucha, B. M. et al. Ataxia-telangiectasia with hyper-IgM and Wilms tumor: fatal reaction to irradiation. J. Pediatr. Hematol. Oncol. 32, e28–e30 (2010).

    Article  PubMed  Google Scholar 

  97. Takagi, M. et al. First phase 1 clinical study of olaparib in pediatric patients with refractory solid tumors. Cancer 128, 2949–2957 (2022).

    Article  CAS  PubMed  Google Scholar 

  98. Hohenstein, P., Pritchard-Jones, K. & Charlton, J. The yin and yang of kidney development and Wilms’ tumors. Genes Dev. 29, 467–482 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Treger, T. D., Chowdhury, T., Pritchard-Jones, K. & Behjati, S. The genetic changes of Wilms tumour. Nat. Rev. Nephrol. 15, 240–251 (2019).

    Article  PubMed  Google Scholar 

  100. Fontaine, S. D. et al. A very long-acting PARP inhibitor suppresses cancer cell growth in DNA repair-deficient tumor models. Cancer Res. 81, 1076–1086 (2021).

    Article  CAS  PubMed  Google Scholar 

  101. Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Degasperi, A. et al. Substitution mutational signatures in whole-genome-sequenced cancers in the UK population. Science 376, abl9283 (2022).

    Article  Google Scholar 

  103. Dizman, N., Philip, E. J. & Pal, S. K. Genomic profiling in renal cell carcinoma. Nat. Rev. Nephrol. 16, 435–451 (2020).

    Article  PubMed  Google Scholar 

  104. Jonasch, E., Walker, C. L. & Rathmell, W. K. Clear cell renal cell carcinoma ontogeny and mechanisms of lethality. Nat. Rev. Nephrol. 17, 245–261 (2021).

    Article  CAS  PubMed  Google Scholar 

  105. Riazalhosseini, Y. & Lathrop, M. Precision medicine from the renal cancer genome. Nat. Rev. Nephrol. 12, 655–666 (2016).

    Article  CAS  PubMed  Google Scholar 

  106. Scelo, G. et al. Variation in genomic landscape of clear cell renal cell carcinoma across Europe. Nat. Commun. 5, 5135 (2014).

    Article  CAS  PubMed  Google Scholar 

  107. DiGiovanna, J. J. & Kraemer, K. H. Shining a light on xeroderma pigmentosum. J. Invest. Dermatol. 132, 785–796 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Yurchenko, A. A. et al. XPC deficiency increases risk of hematologic malignancies through mutator phenotype and characteristic mutational signature. Nat. Commun. 11, 5834 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Nikolaev, S., Yurchenko, A. A. & Sarasin, A. Increased risk of internal tumors in DNA repair-deficient xeroderma pigmentosum patients: analysis of four international cohorts. Orphanet J. Rare Dis. 17, 104 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Boulma, R. et al. Xeroderma pigmentosum and renal leiomyosarcoma: a very rare case report association. Int. J. Surg. Case Rep. 78, 310–313 (2021).

    Article  PubMed  Google Scholar 

  111. Kraemer, K. H. et al. Xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome: a complex genotype-phenotype relationship. Neuroscience 145, 1388–1396 (2007).

    Article  CAS  PubMed  Google Scholar 

  112. Sumiyoshi, M. et al. Alert regarding cisplatin-induced severe adverse events in cancer patients with xeroderma pigmentosum. Intern. Med. 56, 979–982 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Carneiro, M. C., Kimura, T. C., Tolentino, E. S., Pieralisi, N. & Veltrini, V. C. Unusual intraoral cancer with unexpected outcome in a patient with xeroderma pigmentosum: an alert for antineoplastic treatment. Oral. Surg. Oral. Med. Oral. Pathol. Oral. Radiol. 129, e1–e11 (2020).

    Article  PubMed  Google Scholar 

  114. Gilbar, P. J. & Pokharel, K. Severe cisplatin-induced renal toxicity in a patient with xeroderma pigmentosum. J. Oncol. Pharm. Pract. 28, 466–470 (2022).

    Article  CAS  PubMed  Google Scholar 

  115. Laugel, V. et al. Mutation update for the CSB/ERCC6 and CSA/ERCC8 genes involved in Cockayne syndrome. Hum. Mutat. 31, 113–126 (2010).

    Article  CAS  PubMed  Google Scholar 

  116. Licht, C. L., Stevnsner, T. & Bohr, V. A. Cockayne syndrome group B cellular and biochemical functions. Am. J. Hum. Genet. 73, 1217–1239 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Nance, M. A. & Berry, S. A. Cockayne syndrome: review of 140 cases. Am. J. Med. Genet. 42, 68–84 (1992).

    Article  CAS  PubMed  Google Scholar 

  118. Wilson, B. T. et al. The Cockayne syndrome natural history (CoSyNH) study: clinical findings in 102 individuals and recommendations for care. Genet. Med. 18, 483–493 (2016).

    Article  PubMed  Google Scholar 

  119. van den Heuvel, D., van der Weegen, Y., Boer, D. E. C., Ogi, T. & Luijsterburg, M. S. Transcription-coupled DNA repair: from mechanism to human disorder. Trends Cell Biol. 31, 359–371 (2021).

    Article  PubMed  Google Scholar 

  120. Ben Chehida, A., Ghali, N., Ben Abdelaziz, R., Ben Moussa, F. & Tebib, N. Renal involvement in 2 siblings with Cockayne syndrome. Iran. J. Kidney Dis. 11, 253–255 (2017).

    PubMed  Google Scholar 

  121. Kubota, M. et al. Nationwide survey of Cockayne syndrome in Japan: incidence, clinical course and prognosis. Pediatr. Int. 57, 339–347 (2015).

    Article  PubMed  Google Scholar 

  122. Stern-Delfils, A. et al. Renal disease in Cockayne syndrome. Eur. J. Med. Genet. 63, 103612 (2020).

    Article  PubMed  Google Scholar 

  123. Kralund, H. H. et al. Xeroderma pigmentosum-trichothiodystrophy overlap patient with novel XPD/ERCC2 mutation. Rare Dis. 1, e24932 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Kondo, D. et al. Elevated urinary levels of 8-Hydroxy-2’-deoxyguanosine in a Japanese child of xeroderma pigmentosum/Cockayne syndrome complex with infantile onset of nephrotic syndrome. Tohoku J. Exp. Med. 239, 231–235 (2016).

    Article  CAS  PubMed  Google Scholar 

  125. Jaspers, N. G. et al. First reported patient with human ERCC1 deficiency has cerebro-oculo-facio-skeletal syndrome with a mild defect in nucleotide excision repair and severe developmental failure. Am. J. Hum. Genet. 80, 457–466 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Apelt, K. et al. ERCC1 mutations impede DNA damage repair and cause liver and kidney dysfunction in patients. J. Exp. Med. 218, e20200622 (2021).

    Article  CAS  PubMed  Google Scholar 

  127. Faivre, L. et al. Association of complementation group and mutation type with clinical outcome in Fanconi anemia. European Fanconi Anemia Research Group. Blood 96, 4064–4070 (2000).

    CAS  PubMed  Google Scholar 

  128. Sathyanarayana, V. et al. Patterns and frequency of renal abnormalities in Fanconi anaemia: implications for long-term management. Pediatr. Nephrol. 33, 1547–1551 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Kratz, K. et al. Deficiency of FANCD2-associated nuclease KIAA1018/FAN1 sensitizes cells to interstrand crosslinking agents. Cell 142, 77–88 (2010).

    Article  CAS  PubMed  Google Scholar 

  130. Liu, T., Ghosal, G., Yuan, J., Chen, J. & Huang, J. FAN1 acts with FANCI-FANCD2 to promote DNA interstrand cross-link repair. Science 329, 693–696 (2010).

    Article  CAS  PubMed  Google Scholar 

  131. MacKay, C. et al. Identification of KIAA1018/FAN1, a DNA repair nuclease recruited to DNA damage by monoubiquitinated FANCD2. Cell 142, 65–76 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Smogorzewska, A. et al. A genetic screen identifies FAN1, a Fanconi anemia-associated nuclease necessary for DNA interstrand crosslink repair. Mol. Cell 39, 36–47 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Thongthip, S. et al. Fan1 deficiency results in DNA interstrand cross-link repair defects, enhanced tissue karyomegaly, and organ dysfunction. Genes Dev. 30, 645–659 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Lachaud, C. et al. Karyomegalic interstitial nephritis and DNA damage-induced polyploidy in Fan1 nuclease-defective knock-in mice. Genes Dev. 30, 639–644 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Zhou, W. et al. FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair. Nat. Genet. 44, 910–915 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Deshmukh, A. L. et al. FAN1, a DNA repair nuclease, as a modifier of repeat expansion disorders. J. Huntingt. Dis. 10, 95–122 (2021).

    Article  CAS  Google Scholar 

  137. Boerkoel, C. F. et al. Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia. Nat. Genet. 30, 215–220 (2002).

    Article  CAS  PubMed  Google Scholar 

  138. Bansbach, C. E., Betous, R., Lovejoy, C. A., Glick, G. G. & Cortez, D. The annealing helicase SMARCAL1 maintains genome integrity at stalled replication forks. Genes Dev. 23, 2405–2414 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Simon, A. J. et al. Novel SMARCAL1 bi-allelic mutations associated with a chromosomal breakage phenotype in a severe SIOD patient. J. Clin. Immunol. 34, 76–83 (2014).

    Article  CAS  PubMed  Google Scholar 

  140. Boerkoel, C. F. et al. Manifestations and treatment of Schimke immuno-osseous dysplasia: 14 new cases and a review of the literature. Eur. J. Pediatr. 159, 1–7 (2000).

    Article  CAS  PubMed  Google Scholar 

  141. Weemaes, C. M., Smeets, D. F., Horstink, M., Haraldsson, A. & Bakkeren, J. A. Variants of Nijmegen breakage syndrome and ataxia telangiectasia. Immunodeficiency 4, 109–111 (1993).

    CAS  PubMed  Google Scholar 

  142. McWhir, J., Selfridge, J., Harrison, D. J., Squires, S. & Melton, D. W. Mice with DNA repair gene (ERCC-1) deficiency have elevated levels of p53, liver nuclear abnormalities and die before weaning. Nat. Genet. 5, 217–224 (1993).

    Article  CAS  PubMed  Google Scholar 

  143. Weeda, G. et al. Disruption of mouse ERCC1 results in a novel repair syndrome with growth failure, nuclear abnormalities and senescence. Curr. Biol. 7, 427–439 (1997).

    Article  CAS  PubMed  Google Scholar 

  144. Tian, M., Shinkura, R., Shinkura, N. & Alt, F. W. Growth retardation, early death, and DNA repair defects in mice deficient for the nucleotide excision repair enzyme XPF. Mol. Cell Biol. 24, 1200–1205 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Dolle, M. E. et al. Broad segmental progeroid changes in short-lived Ercc1−/Δ7 mice. Pathobiol. Aging Age Relat. Dis. 1, 7219 (2011).

    Article  Google Scholar 

  146. Selfridge, J., Hsia, K. T., Redhead, N. J. & Melton, D. W. Correction of liver dysfunction in DNA repair-deficient mice with an ERCC1 transgene. Nucleic Acids Res. 29, 4541–4550 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Braun, F. et al. Loss of genome maintenance accelerates podocyte damage. bioRxiv https://doi.org/10.1101/2020.09.13.295303 (2022).

    Article  Google Scholar 

  148. Mulderrig, L. & Garaycoechea, J. I. XPF-ERCC1 protects liver, kidney and blood homeostasis outside the canonical excision repair pathways. PLoS Genet. 16, e1008555 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Lachaud, C. et al. Ubiquitinated Fancd2 recruits Fan1 to stalled replication forks to prevent genome instability. Science 351, 846–849 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Harada, Y. N. et al. Postnatal growth failure, short life span, and early onset of cellular senescence and subsequent immortalization in mice lacking the xeroderma pigmentosum group G gene. Mol. Cell Biol. 19, 2366–2372 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. van der Pluijm, I. et al. Impaired genome maintenance suppresses the growth hormone–insulin-like growth factor 1 axis in mice with Cockayne syndrome. PLoS Biol. 5, e2 (2007).

    Article  PubMed  Google Scholar 

  152. Jaarsma, D., van der Pluijm, I., van der Horst, G. T. & Hoeijmakers, J. H. Cockayne syndrome pathogenesis: lessons from mouse models. Mech. Ageing Dev. 134, 180–195 (2013).

    Article  CAS  PubMed  Google Scholar 

  153. Ai, L. et al. Endogenous formaldehyde is a memory-related molecule in mice and humans. Commun. Biol. 2, 446 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Kalasz, H. Biological role of formaldehyde, and cycles related to methylation, demethylation, and formaldehyde production. Mini Rev. Med. Chem. 3, 175–192 (2003).

    Article  CAS  PubMed  Google Scholar 

  155. Nakamura, J. et al. Evidence that endogenous formaldehyde produces immunogenic and atherogenic adduct epitopes. Sci. Rep. 7, 10787 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Pontel, L. B. et al. Endogenous formaldehyde is a hematopoietic stem cell genotoxin and metabolic carcinogen. Mol. Cell 60, 177–188 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Mulderrig, L. et al. Aldehyde-driven transcriptional stress triggers an anorexic DNA damage response. Nature 600, 158–163 (2021).

    Article  CAS  PubMed  Google Scholar 

  158. Xie, K. et al. Yes-associated protein regulates podocyte cell cycle re-entry and dedifferentiation in adriamycin-induced nephropathy. Cell Death Dis. 10, 915 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Ratner, J. N., Balasubramanian, B., Corden, J., Warren, S. L. & Bregman, D. B. Ultraviolet radiation-induced ubiquitination and proteasomal degradation of the large subunit of RNA polymerase II. Implications for transcription-coupled DNA repair. J. Biol. Chem. 273, 5184–5189 (1998).

    Article  CAS  PubMed  Google Scholar 

  160. Bregman, D. B. et al. UV-induced ubiquitination of RNA polymerase II: a novel modification deficient in Cockayne syndrome cells. Proc. Natl Acad. Sci. USA 93, 11586–11590 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Vousden, K. H. & Prives, C. Blinded by the light: the growing complexity of p53. Cell 137, 413–431 (2009).

    Article  CAS  PubMed  Google Scholar 

  162. Jiang, M. et al. Regulation of PUMA-alpha by p53 in cisplatin-induced renal cell apoptosis. Oncogene 25, 4056–4066 (2006).

    Article  CAS  PubMed  Google Scholar 

  163. Jiang, M. et al. Nutlin-3 protects kidney cells during cisplatin therapy by suppressing Bax/Bak activation. J. Biol. Chem. 282, 2636–2645 (2007).

    Article  CAS  PubMed  Google Scholar 

  164. Wei, Q. et al. Activation and involvement of p53 in cisplatin-induced nephrotoxicity. Am. J. Physiol. Renal Physiol. 293, F1282–F1291 (2007).

    Article  CAS  PubMed  Google Scholar 

  165. Yang, C. et al. Transcriptional activation of caspase-6 and -7 genes by cisplatin-induced p53 and its functional significance in cisplatin nephrotoxicity. Cell Death Differ. 15, 530–544 (2008).

    Article  CAS  PubMed  Google Scholar 

  166. Molitoris, B. A. et al. siRNA targeted to p53 attenuates ischemic and cisplatin-induced acute kidney injury. J. Am. Soc. Nephrol. 20, 1754–1764 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Zhang, D. et al. Tubular p53 regulates multiple genes to mediate AKI. J. Am. Soc. Nephrol. 25, 2278–2289 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Megyesi, J., Safirstein, R. L. & Price, P. M. Induction of p21WAF1/CIP1/SDI1 in kidney tubule cells affects the course of cisplatin-induced acute renal failure. J. Clin. Invest. 101, 777–782 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Megyesi, J., Andrade, L., Vieira, J. M. Jr., Safirstein, R. L. & Price, P. M. Positive effect of the induction of p21WAF1/CIP1 on the course of ischemic acute renal failure. Kidney Int. 60, 2164–2172 (2001).

    Article  CAS  PubMed  Google Scholar 

  170. Koyano, T. et al. The p21 dependent G2 arrest of the cell cycle in epithelial tubular cells links to the early stage of renal fibrosis. Sci. Rep. 9, 12059 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  171. De Chiara, L., Conte, C., Antonelli, G. & Lazzeri, E. Tubular cell cycle response upon AKI: revising old and new paradigms to identify novel targets for CKD prevention. Int. J. Mol. Sci. 22, 11093 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  172. Lazzeri, E. et al. Endocycle-related tubular cell hypertrophy and progenitor proliferation recover renal function after acute kidney injury. Nat. Commun. 9, 1344 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Schreibing, F. & Kramann, R. Mapping the human kidney using single-cell genomics. Nat. Rev. Nephrol. 18, 347–360 (2022).

    Article  PubMed  Google Scholar 

  174. Hsu, J. Y. et al. Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15. Nature 550, 255–259 (2017).

    Article  PubMed  Google Scholar 

  175. Mullican, S. E. et al. GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nat. Med. 23, 1150–1157 (2017).

    Article  CAS  PubMed  Google Scholar 

  176. Breen, D. M. et al. GDF-15 neutralization alleviates platinum-based chemotherapy-induced emesis, anorexia, and weight loss in mice and nonhuman primates. Cell Metab. 32, 938–950 e936 (2020).

    Article  CAS  PubMed  Google Scholar 

  177. Manning, D. K. et al. Loss of the ciliary kinase Nek8 causes left-right asymmetry defects. J. Am. Soc. Nephrol. 24, 100–112 (2013).

    Article  CAS  PubMed  Google Scholar 

  178. Hirooka, M., Hirota, M. & Kamada, M. Renal lesions in Cockayne syndrome. Pediatr. Nephrol. 2, 239–243 (1988).

    Article  CAS  PubMed  Google Scholar 

  179. Funaki, S., Takahashi, S., Murakami, H., Harada, K. & Kitamura, H. Cockayne syndrome with recurrent acute tubulointerstitial nephritis. Pathol. Int. 56, 678–682 (2006).

    Article  PubMed  Google Scholar 

  180. Reiss, U. et al. Nephrotic syndrome, hypertension, and adrenal failure in atypical Cockayne syndrome. Pediatr. Nephrol. 10, 602–605 (1996).

    Article  CAS  PubMed  Google Scholar 

  181. Sato, H. et al. Renal lesions in Cockayne’s syndrome. Clin. Nephrol. 29, 206–209 (1988).

    CAS  PubMed  Google Scholar 

  182. Niedernhofer, L. J. et al. A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis. Nature 444, 1038–1043 (2006).

    Article  CAS  PubMed  Google Scholar 

  183. Chrzanowska, K. H., Gregorek, H., Dembowska-Baginska, B., Kalina, M. A. & Digweed, M. Nijmegen breakage syndrome (NBS). Orphanet J. Rare Dis. 7, 13 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  184. Reiling, E. et al. The progeroid phenotype of Ku80 deficiency is dominant over DNA-PKCS deficiency. PLoS One 9, e93568 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank Dr. Peter Hohenstein for valuable discussions. Work in the lab of J.I.G. is funded by an ERC starting grant (101041308) from the European Research Council. Work in the lab of M.S.L. is funded by an ENW-VICI (VI.C.212.005) grant from the Dutch Research Council (NWO) and an ERC consolidator grant (101043815) from the European Research Council.

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Glossary

Adducts

Covalent attachments of a chemical moiety to DNA.

Complementation groups

In genetics, refer to groups of mutations that do not complement each other to produce a mutant phenotype. Groups of mutations that fail to complement one another are assumed to have mutations in the same gene. This grouping enabled the classification of patients with genetic disorders before the causative gene was identified (for example, xerodema pigmentosum complementation group A, XPA).

DNA damage

A modification of DNA that changes its coding properties or normal function in transcription or replication.

DNA double-strand breaks

(DSBs). A type of DNA damage that arises when both strands of the DNA duplex are severed, often as the result of ionizing radiation.

Homologous recombination

An error-free form of DSB repair during which there is an exchange of strands between a single-stranded DNA and a homologous double-stranded DNA.

Mutational signature

Characteristic combinations of mutation types that arise from specific mutagenesis processes, including exogenous and endogenous genotoxin exposures, defective DNA repair pathways, DNA replication infidelity and DNA enzymatic editing.

Non-epistatic

A relationship between genes, in which one gene does not mask or hide the visible output, or phenotype, of another gene.

Non-homologous end-joining

(NHEJ). A form of DSB repair during which broken DNA ends are ligated; the prominent pathway for repairing DSBs in higher eukaryotic cells.

Origin firing

The initiation of replication that takes place at specialized starts sites, or replication origins.

Repeat expansions

Mutations that arise on repetitive DNA sequences, often owing to slippage during replication.

Replication forks

Multiprotein complexes with DNA helicase and synthesis activities that are responsible for DNA replication.

Transcription-coupled repair

(TC-NER). A sub-pathway of NER during which transcription-blocking DNA lesions are removed from the transcribed strand of an active gene.

Transversion

A point mutation in DNA in which a purine (A or G) is changed to a pyrimidine (C or T), or vice versa.

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Garaycoechea, J.I., Quinlan, C. & Luijsterburg, M.S. Pathological consequences of DNA damage in the kidney. Nat Rev Nephrol 19, 229–243 (2023). https://doi.org/10.1038/s41581-022-00671-z

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