DNA Interstrand Crosslink Repair Mechanisms

DNA interstrand crosslinks (ICLs) are highly cytotoxic lesions formed by covalent bonding between opposite DNA strands, obstructing essential processes such as replication and transcription. Repair of ICLs requires a coordinated multistep pathway commencing with lesion recognition and incision (‘unhooking’) of one DNA strand by specialised endonucleases. The resulting gap is traversed by translesion synthesis polymerases that bypass the attached fragment, followed by excision of the residual adduct and restoration of duplex integrity via homologous recombination. Central to this process is the Fanconi anaemia (FA) pathway, in which FA core complex proteins orchestrate monoubiquitination of FANCD2–FANCI and recruitment of nucleases including XPF–ERCC1 and FAN1. Additional factors such as structure-specific nucleases, SNM1 exonucleases and replication protein A modulate incision and processing of damaged forks. Defects in these repair pathways underpin hereditary syndromes and influence cellular responses to crosslinking chemotherapeutics, highlighting the clinical importance of delineating ICL repair mechanisms.

Research from Nature Portfolio

Recent studies have illuminated the regulation of the FAN1 nuclease during replication-coupled ICL repair. The discovery of a novel PCNA-interacting peptide motif within FAN1, in conjunction with its ubiquitin-binding zinc finger (UBZ) domain, revealed a mechanism by which FAN1 is recruited to ubiquitylated PCNA at stalled replication forks. This targeted recruitment stabilises fork progression and prevents collapse independently of homologous recombination factors such as BRCA2. These insights not only clarify how cells maintain genomic integrity in the face of crosslink damage but also identify FAN1–PCNA interactions as potential therapeutic targets for sensitising BRCA-deficient tumours to crosslinking agents.

DNA Interstrand Crosslink Repair Mechanisms publication trend

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

Technical terms

DNA interstrand crosslink (ICL): A covalent linkage joining bases on opposite DNA strands, blocking strand separation.

Unhooking: Endonucleolytic incision of one DNA strand around an ICL to detach the lesion.

Fanconi anaemia pathway: A network of proteins that detect ICLs and coordinate nucleolytic incision, lesion bypass and repair.

Translesion synthesis (TLS): The process by which specialised polymerases replicate past DNA lesions at the expense of reduced fidelity.

Homologous recombination (HR): A high-fidelity repair mechanism using a homologous template to restore DNA duplex continuity.

Ubiquitin-binding zinc finger (UBZ) domain: A protein motif that recognises ubiquitinated substrates, facilitating recruitment to DNA damage sites.

Proliferating cell nuclear antigen (PCNA): A ring-shaped clamp that tethers polymerases and repair factors to DNA during replication.

References

1. FAN1 interaction with ubiquitylated PCNA alleviates replication stress and preserves genomic integrity independently of BRCA2. Nature Communications (2017).
2. A clickable melphalan for monitoring DNA interstrand crosslink accumulation and detecting ICL repair defects in Fanconi anemia patient cells. Nucleic Acids Research (2023).
3. Cell-active small molecule inhibitors validate the SNM1A DNA repair nuclease as a cancer target. Chemical Science (2024).
4. RPA activates the XPF‐ERCC1 endonuclease to initiate processing of DNA interstrand crosslinks. The EMBO Journal (2017).
5. Mechanisms of interstrand DNA crosslink repair and human disorders. Genes and Environment (2016).