DNA Repair Mechanisms in Genetic Disorders

Genomic integrity is continually challenged by endogenous and environmental insults, leading to a spectrum of DNA lesions that, if unrepaired, precipitate genetic disorders and cancer predisposition. Core repair pathways include nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR) and double-strand break (DSB) repair through homologous recombination (HR) or non-homologous end joining (NHEJ). Within NER, transcription-coupled repair (TCR) serves to remove helix-distorting lesions that stall RNA polymerase II, protecting actively transcribed genes. BER addresses oxidative and alkylation damage via lesion-specific glycosylases and coordinated downstream enzymes. MMR corrects replication errors, while HR and NHEJ resolve DSBs arising from replication stress or ionising radiation. Deficiencies in these pathways underlie disorders such as xeroderma pigmentosum, Cockayne syndrome, ataxia-telangiectasia and hereditary breast and ovarian cancer. Beyond classical enzyme defects, recent research emphasises the roles of chromatin remodelling, R-loop homeostasis and epigenomic regulation in shaping repair outcomes. Insights into pathway choice, lesion recognition and age-related epigenetic drift inform both mechanistic understanding and translational strategies, including targeted gene correction and modulation of repair kinetics to alleviate disease phenotypes.

Research from Nature Portfolio

Recent studies have elucidated how transcription-coupled repair factor deficiencies provoke genome instability via R-loop accumulation. Stalling of RNA polymerase II at repetitive T-runs creates persistent RNA–DNA hybrids in human neuronal genes, explaining the severe neurodevelopmental defects of Cockayne syndrome relative to murine models. Separately, cell-cycle and damage-induced phosphorylation of the CSB chromatin remodeller by ATM and CDK2 orchestrates DSB repair pathway choice. This regulation modulates chromatin accessibility, limits recruitment of 53BP1 effectors and promotes BRCA1 accumulation, thereby steering breaks towards homologous recombination rather than non-homologous end joining.

DNA Repair Mechanisms in Genetic Disorders publication trend

The graph below shows the total number of articles in dna repair mechanisms in genetic disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Transcription-coupled repair (TCR): A subpathway of NER that specifically removes lesions blocking RNA polymerase II on active genes.

R-loop: A three-stranded nucleic acid structure formed when nascent RNA hybridises to the DNA template strand, displacing the non-template strand.

Chromatin remodelling: ATP-dependent alteration of nucleosome positioning to regulate accessibility of DNA repair factors.

Break-induced replication (BIR): A homologous recombination pathway that restarts collapsed replication forks using a homologous template.

Epigenetic clock: A biomarker of biological age based on DNA methylation patterns at specific CpG sites.

References

1. Cockayne Syndrome Linked to Elevated R-Loops Induced by Stalled RNA Polymerase II during Transcription Elongation. Nature Communications (2024).
2. ATM and CDK2 control chromatin remodeler CSB to inhibit RIF1 in DSB repair pathway choice. Nature Communications (2017).
3. Epigenomic signature of accelerated ageing in progeroid Cockayne syndrome. Aging Cell (2023).
4. HiPSC-derived 3D neural models reveal neurodevelopmental pathomechanisms of the Cockayne Syndrome B. Cellular and Molecular Life Sciences (2024).
5. CSB Regulates Pathway Choice in Response to DNA Replication Stress Induced by Camptothecin. International Journal of Molecular Sciences (2023).