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TitleRAD51 protects abasic sites to prevent replication fork breakage.
Journal, issue, pagesMol Cell, Vol. 84, Issue 16, Page 3026-3043.e11, Year 2024
Publish dateAug 22, 2024
AuthorsYodhara Wijesekara Hanthi / Miguel Angel Ramirez-Otero / Robert Appleby / Anna De Antoni / Luay Joudeh / Vincenzo Sannino / Salli Waked / Alessandra Ardizzoia / Viviana Barra / Daniele Fachinetti / Luca Pellegrini / Vincenzo Costanzo /
PubMed AbstractAbasic 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 ...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.
External linksMol Cell / PubMed:39178838
MethodsEM (helical sym.)
Resolution3.2 - 3.4 Å
Structure data

19050

8rcd

EMDB-19050, PDB-8rcd:
RAD51 nucleoprotein filament on abasic single-stranded DNA
Method: EM (helical sym.) / Resolution: 3.2 Å

19051

8rcf

EMDB-19051, PDB-8rcf:
RAD51 nucleoprotein filament on double-stranded abasic DNA
Method: EM (helical sym.) / Resolution: 3.4 Å

Chemicals

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

ChemComp-CA:
Unknown entry

Source
  • homo sapiens (human)
KeywordsDNA BINDING PROTEIN / Homologous recombination / DNA replication / abasic DNA

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