RAD51 protects abasic sites to prevent replication fork breakage

Abasic sites are DNA lesions repaired by base excision repair. Cleavage of unrepaired abasic sites in single-stranded DNA (ssDNA) can lead to chromosomal breakage during DNA replication. How rupture of abasic DNA is prevented remains poorly understood. Here, using cryoelectron microscopy (cryo-EM), Xenopus laevis egg extracts, and human cells, we show that RAD51 nucleofilaments specifically recognize and protect abasic sites, which increase RAD51 association rate to DNA. In the absence of BRCA2 or RAD51, abasic sites accumulate as a result of DNA base methylation, oxidation, and deamination, inducing abasic ssDNA gaps that make replicating DNA fibers sensitive to APE1. RAD51 assembled on abasic DNA prevents abasic site cleavage by the MRE11-RAD50 complex, suppressing replication fork breakage triggered by an excess of abasic sites or POLθ polymerase inhibition. Our study highlights the critical role of BRCA2 and RAD51 in safeguarding against unrepaired abasic sites in DNA templates stemming from base alterations, ensuring genomic stability.

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Publication Details

Journal
Molecular Cell
Published
2024-08-01
DOI
https://doi.org/10.1016/j.molcel.2024.07.004
Citations
39
Primary Topic
DNA Repair Mechanisms
Type
article
Field-Weighted Citation Impact
9.12

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article

RAD51 protects abasic sites to prevent replication fork breakage

Miguel Angel Ramírez-Otero, Daniele Fachinetti, Luay Joudeh, Vincenzo Sannino et al.
39 citations
Molecular Cell
DNA Repair Mechanisms
9.12
article

RAD51 protects abasic sites to prevent replication fork breakage

Miguel Angel Ramírez-Otero, Daniele Fachinetti, Luay Joudeh, Vincenzo Sannino, Vincenzo Costanzo, Viviana Barra, Yodhara Wijesekara Hanthi, Luca Pellegrini, Anna De Antoni, Robert E Appleby, Salli Waked, Alessandra Ardizzoia
article en
39 citations

Abstract

Abasic sites are DNA lesions repaired by base excision repair. Cleavage of unrepaired abasic sites in single-stranded DNA (ssDNA) can lead to chromosomal breakage during DNA replication. How rupture of abasic DNA is prevented remains poorly understood. Here, using cryoelectron microscopy (cryo-EM), Xenopus laevis egg extracts, and human cells, we show that RAD51 nucleofilaments specifically recognize and protect abasic sites, which increase RAD51 association rate to DNA. In the absence of BRCA2 or RAD51, abasic sites accumulate as a result of DNA base methylation, oxidation, and deamination, inducing abasic ssDNA gaps that make replicating DNA fibers sensitive to APE1. RAD51 assembled on abasic DNA prevents abasic site cleavage by the MRE11-RAD50 complex, suppressing replication fork breakage triggered by an excess of abasic sites or POLθ polymerase inhibition. Our study highlights the critical role of BRCA2 and RAD51 in safeguarding against unrepaired abasic sites in DNA templates stemming from base alterations, ensuring genomic stability.

Molecular CellVol. 84(16)
Centre National de la Recherche Scientifique (FR), University of Cambridge (GB), Université Paris Sciences et Lettres (FR), IFOM (IT), Biologie cellulaire et Cancer (FR), Institut Curie (FR)
Giovanni Armenise-Harvard Foundation, Wellcome Trust, University of Cambridge, Associazione Italiana per la Ricerca sul Cancro, Biotechnology and Biological Sciences Research Council
Zero hunger
Openalex Percentile: Top 1%
DNA Repair Mechanisms
9.12
DOIOpen Access PDFOpenAlex
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