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Tirman, Stephanie; Quinet, Annabel; Wood, Matthew; Meroni, Alice; Cybulla, Emily; Jackson, Jessica; Pegoraro, Silvia; Simoneau, Antoine; Zou, Lee; Vindigni, Alessandro
Molecular cell, 10/2021, Letnik: 81, Številka: 19Journal Article
PRIMPOL repriming allows DNA replication to skip DNA lesions, leading to ssDNA gaps. These gaps must be filled to preserve genome stability. Using a DNA fiber approach to directly monitor gap filling, we studied the post-replicative mechanisms that fill the ssDNA gaps generated in cisplatin-treated cells upon increased PRIMPOL expression or when replication fork reversal is defective because of SMARCAL1 inactivation or PARP inhibition. We found that a mechanism dependent on the E3 ubiquitin ligase RAD18, PCNA monoubiquitination, and the REV1 and POLζ translesion synthesis polymerases promotes gap filling in G2. The E2-conjugating enzyme UBC13, the RAD51 recombinase, and REV1-POLζ are instead responsible for gap filling in S, suggesting that temporally distinct pathways of gap filling operate throughout the cell cycle. Furthermore, we found that BRCA1 and BRCA2 promote gap filling by limiting MRE11 activity and that simultaneously targeting fork reversal and gap filling enhances chemosensitivity in BRCA-deficient cells. Display omitted •Two temporally distinct pathways fill ssDNA gaps in human cells•RAD18, PCNA monoubiquitination, and REV1-POLζ promote gap filling in G2•UBC13, RAD51, and REV1-POLζ promote gap filling in S•BRCA1 and BRCA2 promote gap filling by limiting MRE11 activity in S and G2 PRIMPOL generates ssDNA gaps, which must be filled to maintain genome stability. Tirman et al. show that two distinct pathways fill ssDNA gaps throughout the cell cycle in human cells and that BRCA proteins promote gap filling by limiting MRE11 activity. Disruption of these pathways enhances genome instability and chemosensitivity.
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