Base Excision Repair Mechanisms in DNA Maintenance Systems

Base excision repair (BER) is a fundamental pathway that safeguards genomic integrity by detecting and removing small base lesions arising from oxidation, alkylation, deamination or spontaneous base loss. The process is initiated by specialised DNA glycosylases that excise damaged bases, generating abasic (AP) sites. AP endonucleases then cleave the phosphodiester backbone adjacent to these sites, creating single-strand breaks that are further processed by lyases, DNA polymerases and ligases. This coordinated cascade restores DNA continuity with high fidelity and minimal disruption to chromatin structure. Recent advances have elucidated how BER interfaces with transcription, replication and epigenetic reprogramming, and how post-translational modifications regulate the recruitment and turnover of repair enzymes. Understanding these mechanisms is critical for appreciating how cells prevent mutagenesis, how BER dysfunction contributes to ageing and cancer, and how targeted manipulation of BER factors may enhance chemotherapeutic efficacy or modulate immune responses.

Research from Nature Portfolio

Recent studies have revealed that covalent attachment of poly-ADP-ribose (PAR) moieties to BER proteins accelerates repair by promoting dissociation of enzymes from DNA. This modification, mediated by PARP1 and PARP2, coordinates BER with active DNA demethylation by TET-TDG enzymes and ensures efficient resolution of both programmed and random lesions in embryonic stem cells. Concurrent structural work has provided high-resolution snapshots of human AP endonuclease 1 (APE1) engaging diverse substrates. These structures elucidate how one active site accommodates both AP site incision and 3′→5′ exonuclease proofreading of mismatches, revealing DNA bending and intra-helical positioning that underpin versatility in lesion processing.

Base Excision Repair Mechanisms in DNA Maintenance Systems publication trend

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

Technical terms

Base excision repair (BER): A multi-step pathway for removal and replacement of single damaged bases in DNA.

Abasic site (AP site): A sugar–phosphate position in DNA where the base has been enzymatically or spontaneously removed.

DNA glycosylase: An enzyme that recognises and excises specific damaged bases, creating an AP site.

AP endonuclease (APE1): The enzyme that cleaves the DNA backbone immediately 5′ to an AP site, facilitating downstream repair.

PARylation: The covalent addition of poly-ADP-ribose chains to target proteins, often mediated by PARP enzymes, modulating protein–DNA interactions.

Replication fork: The junction between unwound parental strands and growing daughter strands during DNA replication.

References

1. Covalent PARylation of DNA base excision repair proteins regulates DNA demethylation. Nature Communications (2024).
2. Molecular snapshots of APE1 proofreading mismatches and removing DNA damage. Nature Communications (2018).
3. Mechanistic insight into AP-endonuclease 1 cleavage of abasic sites at stalled replication fork mimics. Nucleic Acids Research (2023).
4. Unrepaired base excision repair intermediates in template DNA strands trigger replication fork collapse and PARP inhibitor sensitivity. The EMBO Journal (2023).
5. Apex1 safeguards genomic stability to ensure a cytopathic T cell fate in autoimmune disease models. Journal of Clinical Investigation (2024).