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bioRxiv · 10.1101/2024.10.14.618148

Mechanistic Insights into Alcohol-Induced DNA Crosslink Repair by the Fanconi Anemia Nuclease Slx4-Xpf-Ercc1

Havlikova, J.·Dejmek, M.·Huskova, A.·Allan, A.·Boura, E.·Nencka, R.·Silhan, J.
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Abstract

During cell division, DNA replication stalls upon alcohol-derived interstrand crosslink, employing DNA repair pathways. Acetaldehyde, a toxic metabolite of alcohol, can induce DNA crosslinks between complementary DNA strands, causing significant genomic instability. The repair of acetaldehyde DNA crosslinks (AA-ICLs) is vital for maintaining genome integrity and preventing mutagenic events. The Fanconi anemia (FA) repair pathways involvement in fixing the AA-ICLs is crucial, ensuring cellular homeostasis and safeguarding genomic stability. Dysregulation of the FA pathway has been linked to Fanconi anemia, a rare genetic disorder characterized by hypersensitivity to DNA-damaging agents, including acetaldehyde. However, the precise mechanism of the repair and incision of AA-ICLs is unknown. Here, we demonstrate the role of the FA pathway nuclease SLX4-XPF-ERCC1 (SXE) in the repair of AA-ICL. We have generated site-specific AA-ICL within the replication fork, and we found SXE to excise the crosslink from the replication fork, bringing evidence of its role in the repair of alcohol-induced DNA lesions. This nuclease complex performs two precise incisions around the lesion. We also demonstrate that the SXE nuclease excises an abasic site interstrand crosslink in a similar manner. Given the evidence in conjunction with previous repair studies that have been conducted, our work suggests that SXE is a versatile nuclease complex.

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Havlikova, J., Dejmek, M., Huskova, A., Allan, A., Boura, E., Nencka, R., Silhan, J.. 2024-10-16. Mechanistic Insights into Alcohol-Induced DNA Crosslink Repair by the Fanconi Anemia Nuclease Slx4-Xpf-Ercc1. https://doi.org/10.1101/2024.10.14.618148

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