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
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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.
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The kidney is exquisitely sensitive to chemotherapeutic and environmental agents that damage DNA, leading to both acute and chronic kidney injury.
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An unexpected and currently incompletely understood link between kidney ciliopathies and the DNA damage response has emerged.
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Genetic DNA repair defects in humans have highlighted DNA crosslinks, DNA breaks and transcription-blocking damage as particularly toxic lesions to the kidney.
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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.
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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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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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DOI: https://doi.org/10.1038/s41581-022-00671-z
