Key Points
-
Homologous recombination maintains genomic stability in mammalian mitotic cells through precise templated repair of DNA double-strand breaks and other lesions. The outcome of homologous recombination is typically precise when the sister chromatid is the donor template.
-
Homologous recombination is a coordinated process involving the RAD51 strand exchange protein and numerous other proteins that promote RAD51 function. RAD51 forms a filament on single-stranded DNA that is generated by end resection.
-
Precise repair is promoted by both regulated expression and activation of factors involved in homologous repair during the S and G2 phases of the cell cycle.
-
Alternative templates for repair that encompass some degree of heterology have the potential to be mutagenic, with the occurrence of loss of heterozygosity or rearrangements. Most rearrangements occur by alternative DNA double-strand break repair pathways that do not involve homology.
-
Mammalian cells that are defective for homologous recombination components have spontaneous and damage-induced genomic instability, mild ionizing radiation sensitivity and severe sensitivity to DNA cross-linking agents.
-
In humans, biallelic defects in the homologous recombination factors breast and ovarian cancer type 2 susceptibility protein (BRCA2), partner and localizer of BRCA2 (PALB2) and BRCA1-interacting protein 1 (BRIP1) result in Fanconi anaemia, and mono-allelic defects in BRCA2, BRCA1, PALB2 and BRIP1 result in a predisposition to breast cancer. Other human tumours are associated with the loss of BRCA2, BRCA1 and PALB2.
Abstract
Mitotic homologous recombination promotes genome stability through the precise repair of DNA double-strand breaks and other lesions that are encountered during normal cellular metabolism and from exogenous insults. As a result, homologous recombination repair is essential during proliferative stages in development and during somatic cell renewal in adults to protect against cell death and mutagenic outcomes from DNA damage. Mutations in mammalian genes encoding homologous recombination proteins, including BRCA1, BRCA2 and PALB2, are associated with developmental abnormalities and tumorigenesis. Recent advances have provided a clearer understanding of the connections between these proteins and of the key steps of homologous recombination and DNA strand exchange.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Hoeijmakers, J. H. DNA damage, aging, and cancer. N. Engl. J. Med. 361, 1475–1485 (2009).
Negrini, S., Gorgoulis, V. G. & Halazonetis, T. D. Genomic instability — an evolving hallmark of cancer. Nature Rev. Mol. Cell Biol. 11, 220–228 (2010).
Liang, F., Han, M., Romanienko, P. J. & Jasin, M. Homology-directed repair is a major double-strand break repair pathway in mammalian cells. Proc. Natl Acad. Sci. USA 95, 5172–5177 (1998). Compares HR and NHEJ repair of a genomic DSB in mammalian cells.
Aquilera, A. & Rothstein, R. Molecular Genetics of Recombination (Springer, Berlin Germany, 2007).
Haber, J. E. Partners and pathways repairing a double-strand break. Trends Genet. 16, 259–264 (2000).
Johnson, R. D. & Jasin, M. Double-strand-break-induced homologous recombination in mammalian cells. Biochem. Soc. Trans. 29, 196–201 (2001).
Sung, P. & Klein, H. Mechanism of homologous recombination: mediators and helicases take on regulatory functions. Nature Rev. Mol. Cell Biol. 7, 739–750 (2006).
Mimitou, E. P. & Symington, L. S. Nucleases and helicases take center stage in homologous recombination. Trends Biochem. Sci. 34, 264–272 (2009).
Lieber, M. R. The mechanism of human nonhomologous DNA end joining. J. Biol. Chem. 283, 1–5 (2008).
Rouet, P., Smih, F. & Jasin, M. Introduction of double-strand breaks into the genome of mouse cells by expression of a rare-cutting endonuclease. Mol. Cell. Biol. 14, 8096–8106 (1994).
Liang, F. & Jasin, M. Ku80 deficient cells exhibit excess degradation of extrachromosomal DNA. J. Biol. Chem. 271, 14405–14411 (1996).
Tsuzuki, T. et al. Targeted disruption of the Rad51 gene leads to lethality in embryonic mice. Proc. Natl Acad. Sci. USA 93, 6236–6240 (1996).
Lim, D.-S. & Hasty, P. A mutation in mouse rad51 results in an early embryonic lethal that is suppressed by a mutation in p53. Mol. Cell. Biol. 16, 7133–7143 (1996). References 12 and 13 provided two of the first indications of a crucial role for HR in mammals.
Sung, P. Catalysis of ATP-dependent homologous DNA pairing and strand exchange by yeast RAD51 protein. Science 265, 1241–1243 (1994).
Baumann, P., Benson, F. E. & West, S. C. Human Rad51 protein promotes ATP-dependent homologous pairing and strand transfer reactions in vitro. Cell 87, 757–766 (1996).
Sung, P. & Robberson, D. L. DNA strand exchange mediated by a RAD51-ssDNA nucleoprotein filament with polarity opposite to that of RecA. Cell 82, 453–461 (1995).
Benson, F. E., Stasiak, A. & West, S. C. Purification and characterization of the human Rad51 protein, an analogue of E. coli RecA. EMBO J. 13, 5764–5771 (1994).
Chen, Z., Yang, H. & Pavletich, N. P. Mechanism of homologous recombination from the RecA-ssDNA/dsDNA structures. Nature 453, 489–494 (2008). Crystal structures of RecA with ssDNA and dsDNA, leading to the discovery that, although stretched, DNA adopts a local B-form DNA-like structure, which restricts the homology search to sequences that can form Watson–Crick base pairs.
Mimitou, E. P. & Symington, L. S. Sae2, Exo1 and Sgs1 collaborate in DNA double-strand break processing. Nature 455, 770–774 (2008).
Zhu, Z., Chung, W. H., Shim, E. Y., Lee, S. E. & Ira, G. Sgs1 helicase and two nucleases Dna2 and Exo1 resect DNA double-strand break ends. Cell 134, 981–994 (2008). References 19 and 20 provide evidence for a two-step mechanism for DNA end resection in yeast to initiate HR: initial limited resection by the Mre11 complex and Sae2, followed by processive resection involving either Exo1 or Sgs1.
Nimonkar, A. V., Ozsoy, A. Z., Genschel, J., Modrich, P. & Kowalczykowski, S. C. Human exonuclease 1 and BLM helicase interact to resect DNA and initiate DNA repair. Proc. Natl Acad. Sci. USA 105, 16906–16911 (2008).
Buis, J. et al. Mre11 nuclease activity has essential roles in DNA repair and genomic stability distinct from ATM activation. Cell 135, 85–96 (2008).
Yu, X., Wu, L. C., Bowcock, A. M., Aronheim, A. & Baer, R. The C-terminal (BRCT) domains of BRCA1 interact in vivo with CtIP, a protein implicated in the CtBP pathway of transcriptional repression. J. Biol. Chem. 273, 25388–25392 (1998).
Sartori, A. A. et al. Human CtIP promotes DNA end resection. Nature 450, 509–514 (2007). Discovery that CtIP promotes HR and is related to the yeast protein Sae2, which is involved in DNA end-resection.
Ira, G. et al. DNA end resection, homologous recombination and DNA damage checkpoint activation require CDK1. Nature 431, 1011–1017 (2004).
Aylon, Y., Liefshitz, B. & Kupiec, M. The CDK regulates repair of double-strand breaks by homologous recombination during the cell cycle. EMBO J. 23, 4868–4875 (2004).
Huertas, P., Cortes-Ledesma, F., Sartori, A. A., Aguilera, A. & Jackson, S. P. CDK targets Sae2 to control DNA-end resection and homologous recombination. Nature 455, 689–692 (2008).
Huertas, P. & Jackson, S. P. Human CtIP mediates cell cycle control of DNA end resection and double strand break repair. J. Biol. Chem. 284, 9558–9565 (2009).
Sung, P., Krejci, L., Van Komen, S. & Sehorn, M. G. Rad51 recombinase and recombination mediators. J. Biol. Chem. 278, 42729–42732 (2003).
Wu, L. & Hickson, I. D. The Bloom's syndrome helicase suppresses crossing over during homologous recombination. Nature 426, 870–874 (2003).
Baudat, F. & de Massy, B. Regulating double-stranded DNA break repair towards crossover or non-crossover during mammalian meiosis. Chromosome Res. 15, 565–577 (2007).
Esashi, F. et al. CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair. Nature 434, 598–604 (2005).
Rothkamm, K., Kruger, I., Thompson, L. H. & Lobrich, M. Pathways of DNA double-strand break repair during the mammalian cell cycle. Mol. Cell. Biol. 23, 5706–5715 (2003). Using phosphorylated histone H2AX (γH2AX) as a marker for the repair of DSBs generated by low doses of ionizing radiation, this study shows that NHEJ is important for DSB repair in all cell cycle phases, and HR is important in late S and G2. By contrast, DSBs produced by a replication inhibitor are predominately repaired by HR.
Pellicioli, A., Lee, S. E., Lucca, C., Foiani, M. & Haber, J. E. Regulation of Saccharomyces Rad53 checkpoint kinase during adaptation from DNA damage-induced G2/M arrest. Mol. Cell 7, 293–300 (2001).
Pierce, A. J., Hu, P., Han, M., Ellis, N. & Jasin, M. Ku DNA end-binding protein modulates homologous repair of double-strand breaks in mammalian cells. Genes Dev. 15, 3237–3242 (2001).
Allen, C., Kurimasa, A., Brenneman, M. A., Chen, D. J. & Nickoloff, J. A. DNA-dependent protein kinase suppresses double-strand break-induced and spontaneous homologous recombination. Proc. Natl Acad. Sci. USA 99, 3758–3763 (2002).
Weinstock, D. M. & Jasin, M. Alternative pathways for the repair of RAG-induced DNA breaks. Mol. Cell. Biol. 26, 131–139 (2006).
Cox, M. M. et al. The importance of repairing stalled replication forks. Nature 404, 37–41 (2000).
Wyman, C. & Kanaar, R. DNA double-strand break repair: all's well that ends well. Annu. Rev. Genet. 40, 363–383 (2006).
Stark, J. M., Pierce, A. J., Oh, J., Pastink, A. & Jasin, M. Genetic steps of mammalian homologous repair with distinct mutagenic consequences. Mol. Cell. Biol. 24, 9305–9316 (2004).
Bennardo, N., Gunn, A., Cheng, A., Hasty, P. & Stark, J. M. Limiting the persistence of a chromosome break diminishes its mutagenic potential. PLoS Genet. 5, e1000683 (2009).
Johnson, R. D. & Jasin, M. Sister chromatid gene conversion is a prominent double-strand break repair pathway in mammalian cells. EMBO J. 19, 3398–3407 (2000).
Delacote, F., Han, M., Stamato, T. D., Jasin, M. & Lopez, B. S. An xrcc4 defect or wortmannin stimulates homologous recombination specifically induced by double-strand breaks in mammalian cells. Nucleic Acids Res. 30, 3454–3463 (2002).
Nakanishi, K. et al. Human Fanconi anemia monoubiquitination pathway promotes homologous DNA repair. Proc. Natl Acad. Sci. USA 102, 1110–1115 (2005).
Dronkert, M. L. et al. Mouse RAD54 affects DNA double-strand break repair and sister chromatid exchange. Mol. Cell. Biol. 20, 3147–3156 (2000).
Stark, J. M. & Jasin, M. Extensive loss of heterozygosity is suppressed during homologous repair of chromosomal breaks. Mol. Cell. Biol. 23, 733–743 (2003).
Wiese, C., Pierce, A. J., Gauny, S. S., Jasin, M. & Kronenberg, A. Gene conversion is strongly induced in human cells by double-strand breaks and is modulated by the expression of BCL-xL . Cancer Res. 62, 1279–1283 (2002).
Neuwirth, E. A., Honma, M. & Grosovsky, A. J. Interchromosomal crossover in human cells is associated with long gene conversion tracts. Mol. Cell. Biol. 27, 5261–5274 (2007).
Moynahan, M. E. & Jasin, M. Loss of heterozygosity induced by a chromosomal double-strand break. Proc. Natl Acad. Sci. USA 94, 8988–8993 (1997).
Hagstrom, S. A. & Dryja, T. P. Mitotic recombination map of 13cen-13q14 derived from an investigation of loss of heterozygosity in retinoblastomas. Proc. Natl Acad. Sci. USA 96, 2952–2957 (1999).
Elliott, B. & Jasin, M. Repair of double-strand breaks by homologous recombination in mismatch repair-defective mammalian cells. Mol. Cell. Biol. 21, 2671–2682 (2001).
Richardson, C. & Jasin, M. Frequent chromosomal translocations induced by DNA double-strand breaks. Nature 405, 697–700 (2000).
Elliott, B., Richardson, C. & Jasin, M. Chromosomal translocation mechanisms at intronic alu elements in mammalian cells. Mol. Cell 17, 885–894 (2005).
Lieber, M. R., Yu, K. & Raghavan, S. C. Roles of nonhomologous DNA end joining, V(D)J recombination, and class switch recombination in chromosomal translocations. DNA Repair (Amst.) 5, 1234–1245 (2006).
Campbell, P. J. et al. Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. Nature Genet. 40, 722–729 (2008).
Ferguson, D. O. et al. The nonhomologous end-joining pathway of DNA repair is required for genomic stability and the suppression of translocations. Proc. Natl Acad. Sci. USA 97, 6630–6633 (2000).
Weinstock, D. M., Brunet, E. & Jasin, M. Formation of NHEJ-derived reciprocal chromosomal translocations does not require Ku70. Nature Cell Biol. 9, 978–981 (2007).
Wang, J. H. et al. Mechanisms promoting translocations in editing and switching peripheral B cells. Nature 460, 231–236 (2009).
Simsek, D. & Jasin, M. Alternative end-joining is suppressed by the canonical NHEJ component Xrcc4/ligase IV during chromosomal translocation formation. Nature Struct. Mol. Biol. (in the press).
Haaf, T., Golub, E. I., Reddy, G., Radding, C. M. & Ward, D. C. Nuclear foci of mammalian Rad51 recombination protein in somatic cells after DNA damage and its localization in synaptonemal complexes. Proc. Natl Acad. Sci. USA 92, 2298–2302 (1995).
Scully, R. et al. Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell 88, 265–275 (1997). First report to link BRCA1 to RAD51: co-localization of the two proteins is observed in nuclear foci.
Sharan, S. K. et al. Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature 386, 804–810 (1997). First report to link BRCA2 to RAD51 function; early embryonic lethality of Brca2 -mutant mice and radiation sensitivity of Brca2 -mutant embryos are observed.
Moynahan, M. E., Chiu, J. W., Koller, B. H. & Jasin, M. Brca1 controls homology-directed DNA repair. Mol. Cell 4, 511–518 (1999). Shows that BRCA1 deficiency results in HR defects
Moynahan, M. E., Cui, T. X. & Jasin, M. Homology-directed DNA repair, mitomycin-C resistance, and chromosome stability is restored with correction of a Brca1 mutation. Cancer Res. 61, 4842–4850 (2001).
Moynahan, M. E., Pierce, A. J. & Jasin, M. BRCA2 is required for homology-directed repair of chromosomal breaks. Mol. Cell 7, 263–272 (2001). Similarly to reference 63, this study shows that BRCA2 deficiency results in HR defects, although phenotypic differences between BRCA1 and BRCA2 mutants are noted.
Jasin, M. Homologous repair of DNA damage and tumorigenesis: the BRCA connection. Oncogene 21, 8981–8993 (2002).
Pellegrini, L. & Venkitaraman, A. Emerging functions of BRCA2 in DNA recombination. Trends Biochem. Sci. 29, 310–316 (2004).
Gudmundsdottir, K. & Ashworth, A. The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability. Oncogene 25, 5864–5874 (2006).
Moynahan, M. E. The cancer connection: BRCA1 and BRCA2 tumor suppression in mice and humans. Oncogene 21, 8994–9007 (2002).
Evers, B. & Jonkers, J. Mouse models of BRCA1 and BRCA2 deficiency: past lessons, current understanding and future prospects. Oncogene 25, 5885–5897 (2006).
Tutt, A. et al. Mutation in Brca2 stimulates error-prone homology-directed repair of DNA double-strand breaks occurring between repeated sequences. EMBO J. 20, 4704–4716 (2001).
Xia, F. et al. Deficiency of human BRCA2 leads to impaired homologous recombination but maintains normal nonhomologous end joining. Proc. Natl Acad. Sci. USA 98, 8644–8649 (2001).
Honrado, E., Osorio, A., Palacios, J. & Benitez, J. Pathology and gene expression of hereditary breast tumors associated with BRCA1, BRCA2 and CHEK2 gene mutations. Oncogene 25, 5837–5845 (2006).
Christ, N., Moynahan, M. E. & Jasin, M. in Molecular Genetics of Recombination (ed. Rothstein, R.) 363–380 (Springer, Berlin, 2007).
Galkin, V. E. et al. BRCA2 BRC motifs bind RAD51-DNA filaments. Proc. Natl Acad. Sci. USA 102, 8537–8542 (2005).
Davies, O. R. & Pellegrini, L. Interaction with the BRCA2 C terminus protects RAD51-DNA filaments from disassembly by BRC repeats. Nature Struct. Mol. Biol. 14, 475–483 (2007).
Esashi, F., Galkin, V. E., Yu, X., Egelman, E. H. & West, S. C. Stabilization of RAD51 nucleoprotein filaments by the C-terminal region of BRCA2. Nature Struct. Mol. Biol. 14, 468–474 (2007).
Carreira, A. et al. The BRC repeats of BRCA2 modulate the DNA-binding selectivity of RAD51. Cell 136, 1032–1043 (2009). Proposes that BRC repeats of BRCA2 control RAD51–DNA interactions by directing active RAD51 to ssDNA and inhibiting RAD51 nucleation on dsDNA to promote HR.
Pellegrini, L. et al. Insights into DNA recombination from the structure of a RAD51-BRCA2 complex. Nature 420, 287–293 (2002). Crystal structure of a fusion between the BRC4 repeat from BRCA2 with the core domain of RAD51, demonstrating that BRC4 can adopt a structure that mimics a RAD51 self-interaction motif.
Rajendra, E. & Venkitaraman, A. R. Two modules in the BRC repeats of BRCA2 mediate structural and functional interactions with the RAD51 recombinase. Nucleic Acids Res. 38, 82–96 (2009).
Saeki, H. et al. Suppression of the DNA repair defects of BRCA2-deficient cells with heterologous protein fusions. Proc. Natl Acad. Sci. USA 103, 8768–8773 (2006).
Yang, H. et al. BRCA2 function in DNA binding and recombination from a BRCA2-DSS1-ssDNA structure. Science 297, 1837–1848 (2002). Crystal structure of an 800-amino acid domain of BRCA2, showing that BRCA2 is a ssDNA-binding protein.
Yang, H., Li, Q., Fan, J., Holloman, W. K. & Pavletich, N. P. The BRCA2 homologue Brh2 nucleates RAD51 filament formation at a dsDNA-ssDNA junction. Nature 433, 653–657 (2005).
Howlett, N. G. et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science 297, 606–609 (2002). Discovery of biallelic mutations in BRCA2 , with a link to developmental defects and tumours in children, similar to mutations in genes encoding Fanconi anaemia proteins.
Alter, B. P., Rosenberg, P. S. & Brody, L. C. Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. J. Med. Genet. 44, 1–9 (2007).
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).
Xia, B. et al. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol. Cell 22, 719–729 (2006). Identification of PALB2 as a BRCA2-interacting protein with a role in HR.
Oliver, A. W., Swift, S., Lord, C. J., Ashworth, A. & Pearl, L. H. Structural basis for recruitment of BRCA2 by PALB2. EMBO Rep. 10, 990–996 (2009).
Sy, S. M., Huen, M. S., Zhu, Y. & Chen, J. PALB2 regulates recombinational repair through chromatin association and oligomerization. J. Biol. Chem. 284, 18302–18310 (2009).
Zhang, F. et al. PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Curr. Biol. 19, 524–529 (2009).
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).
Xia, B. et al. Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. Nature Genet. 39, 159–161 (2007).
Reid, S. et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nature Genet. 39, 162–164 (2007).
Tischkowitz, M. et al. Analysis of PALB2/FANCN-associated breast cancer families. Proc. Natl Acad. Sci. USA 104, 6788–6793 (2007).
Foulkes, W. D. et al. Identification of a novel truncating PALB2 mutation and analysis of its contribution to early-onset breast cancer in French-Canadian women. Breast Cancer Res. 9, R83 (2007).
Rahman, N. et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nature Genet. 39, 165–167 (2007).
Erkko, H. et al. A recurrent mutation in PALB2 in Finnish cancer families. Nature 446, 316–319 (2007).
Erkko, H. et al. Penetrance analysis of the PALB2 c.1592delT founder mutation. Clin. Cancer Res. 14, 4667–4671 (2008).
Heikkinen, T. et al. The breast cancer susceptibility mutation PALB2 1592delT is associated with an aggressive tumor phenotype. Clin. Cancer Res. 15, 3214–3222 (2009).
Garcia, M. J. et al. Analysis of FANCB and FANCN/PALB2 fanconi anemia genes in BRCA1/2-negative Spanish breast cancer families. Breast Cancer Res. Treat. 113, 545–551 (2009).
Jones, S. et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science 324, 217 (2009).
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).
Reid, L. J. et al. E3 ligase activity of BRCA1 is not essential for mammalian cell viability or homology-directed repair of double-strand DNA breaks. Proc. Natl Acad. Sci. USA 105, 20876–20881 (2008).
Glover, J. N., Williams, R. S. & Lee, M. S. Interactions between BRCT repeats and phosphoproteins: tangled up in two. Trends Biochem. Sci. 29, 579–585 (2004).
Williams, R. S., Green, R. & Glover, J. N. Crystal structure of the BRCT repeat region from the breast cancer- associated protein BRCA1. Nature Struct. Biol. 8, 838–842 (2001).
Manke, I. A., Lowery, D. M., Nguyen, A. & Yaffe, M. B. BRCT repeats as phosphopeptide-binding modules involved in protein targeting. Science 302, 636–639 (2003).
Williams, R. S., Lee, M. S., Hau, D. D. & Glover, J. N. Structural basis of phosphopeptide recognition by the BRCT domain of BRCA1. Nature Struct. Mol. Biol. 11, 519–525 (2004).
Wang, B. et al. Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response. Science 316, 1194–1198 (2007).
Clapperton, J. A. et al. Structure and mechanism of BRCA1 BRCT domain recognition of phosphorylated BACH1 with implications for cancer. Nature Struct. Mol. Biol. 11, 512–518 (2004).
Tischkowitz, M. et al. Pathogenicity of the BRCA1 missense variant M1775K is determined by the disruption of the BRCT phosphopeptide-binding pocket: a multi-modal approach. Eur. J. Hum. Genet. 16, 1820–1832 (2008).
Panier, S. & Durocher, D. Regulatory ubiquitylation in response to DNA double-strand breaks. DNA Repair (Amst.) 8, 436–443 (2009).
Ayoub, N. et al. The carboxyl terminus of Brca2 links the disassembly of Rad51 complexes to mitotic entry. Curr. Biol. 19, 1075–1085 (2009).
Kim, H., Chen, J. & Yu, X. Ubiquitin-binding protein RAP80 mediates BRCA1-dependent DNA damage response. Science 316, 1202–1205 (2007).
Sobhian, B. et al. RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites. Science 316, 1198–1202 (2007).
Huen, M. S. et al. RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly. Cell 131, 901–914 (2007).
Kolas, N. K. et al. Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase. Science 318, 1637–1640 (2007).
Mailand, N. et al. RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell 131, 887–900 (2007).
Wang, B. & Elledge, S. J. Ubc13/Rnf8 ubiquitin ligases control foci formation of the Rap80/Abraxas/Brca1/Brcc36 complex in response to DNA damage. Proc. Natl Acad. Sci. USA 104, 20759–20763 (2007).
Zhao, G. Y. et al. A critical role for the ubiquitin-conjugating enzyme Ubc13 in initiating homologous recombination. Mol. Cell 25, 663–675 (2007).
Huang, J. et al. RAD18 transmits DNA damage signalling to elicit homologous recombination repair. Nature Cell Biol. 11, 592–603 (2009).
Cantor, S. B. et al. BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell 105, 149–160 (2001).
Litman, R. et al. BACH1 is critical for homologous recombination and appears to be the Fanconi anemia gene product FANCJ. Cancer Cell 8, 255–265 (2005).
Yu, X., Chini, C. C., He, M., Mer, G. & Chen, J. The BRCT domain is a phospho-protein binding domain. Science 302, 639–642 (2003).
Cantor, S. et al. The BRCA1-associated protein BACH1 is a DNA helicase targeted by clinically relevant inactivating mutations. Proc. Natl Acad. Sci. USA 101, 2357–2362 (2004).
Bridge, W. L., Vandenberg, C. J., Franklin, R. J. & Hiom, K. The BRIP1 helicase functions independently of BRCA1 in the Fanconi anemia pathway for DNA crosslink repair. Nature Genet. 37, 953–957 (2005).
Kumaraswamy, E. & Shiekhattar, R. Activation of BRCA1/BRCA2-associated helicase BACH1 is required for timely progression through S phase. Mol. Cell. Biol. 27, 6733–6741 (2007).
Youds, J. L. et al. DOG-1 is the Caenorhabditis elegans BRIP1/FANCJ homologue and functions in interstrand cross-link repair. Mol. Cell. Biol. 28, 1470–1479 (2008).
Cheung, I., Schertzer, M., Rose, A. & Lansdorp, P. M. Disruption of dog-1 in Caenorhabditis elegans triggers deletions upstream of guanine-rich DNA. Nature Genet. 31, 405–409 (2002).
Youds, J. L., O'Neil, N. J. & Rose, A. M. Homologous recombination is required for genome stability in the absence of DOG-1 in Caenorhabditis elegans. Genetics 173, 697–708 (2006).
Wu, Y., Shin-ya, K. & Brosh, R. M. Jr. FANCJ helicase defective in Fanconia anemia and breast cancer unwinds G-quadruplex DNA to defend genomic stability. Mol. Cell. Biol. 28, 4116–4128 (2008).
Zhao, Y., Tarailo-Graovac, M., O'Neil, N. J. & Rose, A. M. Spectrum of mutational events in the absence of DOG-1/FANCJ in Caenorhabditis elegans. DNA Repair (Amst.) 7, 1846–1854 (2008).
London, T. B. et al. FANCJ is a structure-specific DNA helicase associated with the maintenance of genomic G/C tracts. J. Biol. Chem. 283, 36132–36139 (2008).
Sommers, J. A. et al. FANCJ uses its motor ATPase to destabilize protein-DNA complexes, unwind triplexes, and inhibit RAD51 strand exchange. J. Biol. Chem. 284, 7505–7517 (2009).
Levitus, M. et al. The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J. Nature Genet. 37, 934–935 (2005).
Levran, O. et al. The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia. Nature Genet. 37, 931–933 (2005).
Seal, S. et al. Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nature Genet. 38, 1239–1241 (2006).
De Nicolo, A. et al. A novel breast cancer-associated BRIP1 (FANCJ/BACH1) germ-line mutation impairs protein stability and function. Clin. Cancer Res. 14, 4672–4680 (2008).
Chen, L., Nievera, C. J., Lee, A. Y. & Wu, X. Cell cycle-dependent complex formation of BRCA1.CtIP.MRN is important for DNA double-strand break repair. J. Biol. Chem. 283, 7713–7720 (2008).
Chen, P. L. et al. Inactivation of CtIP leads to early embryonic lethality mediated by G1 restraint and to tumorigenesis by haploid insufficiency. Mol. Cell. Biol. 25, 3535–3542 (2005).
Yun, M. H. & Hiom, K. CtIP-BRCA1 modulates the choice of DNA double-strand-break repair pathway throughout the cell cycle. Nature 459, 460–463 (2009).
Huen, M. S., Sy, S. M. & Chen, J. BRCA1 and its toolbox for the maintenance of genome integrity. Nature Rev. Mol. Cell Biol. 11, 138–148 (2010).
Fong, P. C. et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123–134 (2009).
Pierce, A. J., Johnson, R. D., Thompson, L. H. & Jasin, M. XRCC3 promotes homology-directed repair of DNA damage in mammalian cells. Genes Dev. 13, 2633–2638 (1999).
Johnson, R. D., Liu, N. & Jasin, M. Mammalian XRCC2 promotes the repair of DNA double-strand breaks by homologous recombination. Nature 401, 397–399 (1999). Shows the importance of sister chromatid recombination for DSB repair in mammalian cells and provides direct evidence for a factor involved in HR repair in mammalian cells.
Carroll, D. Progress and prospects: zinc-finger nucleases as gene therapy agents. Gene Ther. 15, 1463–1468 (2008).
Brunet, E. et al. Chromosomal translocations induced at specified loci in human stem cells. Proc. Natl Acad. Sci. USA 106, 10620–10625 (2009).
Kalb, R. et al. Hypomorphic mutations in the gene encoding a key Fanconi anemia protein, FANCD2, sustain a significant group of FA-D2 patients with severe phenotype. Am. J. Hum. Genet. 80, 895–910 (2007).
Lo Ten Foe, J. R. et al. Somatic mosaicism in Fanconi anemia: molecular basis and clinical significance. Eur. J. Hum. Genet. 5, 137–148 (1997).
Waisfisz, Q. et al. Spontaneous functional correction of homozygous fanconi anaemia alleles reveals novel mechanistic basis for reverse mosaicism. Nature Genet. 22, 379–383 (1999).
DeMarini, D. M., Shelton, M. L., Abu-Shakra, A., Szakmary, A. & Levine, J. G. Spectra of spontaneous frameshift mutations at the hisD3052 allele of Salmonella typhimurium in four DNA repair backgrounds. Genetics 149, 17–36 (1998).
Ikeda, H. et al. Genetic reversion in an acute myelogenous leukemia cell line from a Fanconi anemia patient with biallelic mutations in BRCA2. Cancer Res. 63, 2688–2694 (2003).
Sakai, W. et al. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature 451, 1116–1120 (2008).
Edwards, S. L. et al. Resistance to therapy caused by intragenic deletion in BRCA2. Nature 451, 1111–1115 (2008). References 152 and 153 identify genetic reversion of BRCA2 , which leads to resistance to therapeutic agents.
Auerbach, A. D. Fanconi anaemia and its diagnosis. Mutat. Res. 668, 4–10 (2009).
Wang, W. Emergence of DNA-damage response network consisting of Fanconi anaemia and BRCA proteins. Nature Rev. Genet. 8, 735–748 (2007).
Acknowledgements
The authors thank past and present members of the laboratory, especially E. Kass, and colleagues in the field for discussions. Work in the authors' laboratory is supported the Hecksher Foundation for Children (M.E.M.) and National Institutes for Health grants P01CA94060 (M.E.M and M.J.) and R01GM54668 (M.J.).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Related links
Glossary
- B-form DNA
-
The most common helical DNA structure, also called canonical DNA, comprising two aligned strands of DNA in opposite polarity forming a right-handed helix.
- Non-crossover
-
Homologous recombination in which DNA sequences are copied from the donor strand to the recipient strand without an exchange of genetic information with the recipient strand flanking DNA.
- Holliday junction
-
A structural intermediate formed between four DNA strands during homologous recombination.
- Crossover
-
Resolution of homologous recombination resulting in an exchange of DNA sequences between the donor and recipient.
- Loss of heterozygosity
-
Reduction of genetic information from both maternal and paternal alleles to genetic information from a single parent.
- Centrosome
-
A cytoplasmic organelle that organizes microtubules. Preceding mitosis, the centrosome doubles and then is involved in the generation of the mitotic spindle for subsequent chromosome segregation during mitosis.
- Fanconi anaemia
-
A genetic disorder arising from biallelic mutations in one of 13 different genes, characterized by chromosome instability that typically presents early in life, with developmental disorders, anaemia, bone marrow failure and solid and haematologic malignancy. There is a high degree of clinical variation that depends on both the gene defect and mutation type.
- Somatic mosaicism
-
The existence of more than one genetically distinct population of somatic cells in an organism. This can arise by DNA mutation, chromosome non-disjunction, recombination or the spontaneous reversion of inherited mutations.
- E3 ubiquitin ligase
-
A ubiquitin ligase that, in combination with an E2 ubiquitin-conjugating enzyme, adds ubiquitin (a 76-amino acid protein) to a Lys on a target protein.
Rights and permissions
About this article
Cite this article
Moynahan, M., Jasin, M. Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis. Nat Rev Mol Cell Biol 11, 196–207 (2010). https://doi.org/10.1038/nrm2851
Issue Date:
DOI: https://doi.org/10.1038/nrm2851
This article is cited by
-
Transcription–replication conflicts underlie sensitivity to PARP inhibitors
Nature (2024)
-
Targeted DNA integration in human cells without double-strand breaks using CRISPR-associated transposases
Nature Biotechnology (2023)
-
Functional evaluation of BRCA1/2 variants of unknown significance with homologous recombination assay and integrative in silico prediction model
Journal of Human Genetics (2023)
-
Polλ promotes microhomology-mediated end-joining
Nature Structural & Molecular Biology (2023)
-
Genetic and epigenetic alterations in MGMT gene and correlation with concomitant chemoradiotherapy (CRT) in cervical cancer
Journal of Cancer Research and Clinical Oncology (2023)