To ensure the completion of DNA replication and maintenance of genome integrity, DNA repair factors protect stalled replication forks upon replication stress. Previous studies have identified a critical role for the tumor suppressors BRCA1 and BRCA2 in preventing the degradation of nascent DNA by the MRE11 nuclease after replication stress. Here we show that depletion of SMARCAL1, a SNF2-family DNA translocase that remodels stalled forks, restores replication fork stability and reduces the formation of replication stress-induced DNA breaks and chromosomal aberrations in BRCA1/2-deficient cells. In addition to SMARCAL1, other SNF2-family fork remodelers, including ZRANB3 and HLTF, cause nascent DNA degradation and genomic instability in BRCA1/2-deficient cells upon replication stress. Our observations indicate that nascent DNA degradation in BRCA1/2-deficient cells occurs as a consequence of MRE11-dependent nucleolytic processing of reversed forks generated by fork remodelers. These studies provide mechanistic insights into the processes that cause genome instability in BRCA1/2-deficient cells.

为了确保 DNA 复制的完成和基因组完整性的维护，DNA 修复因子在复制压力下保护停滞的复制叉。先前的研究已经确定了肿瘤抑制因子 BRCA1 和 BRCA2 在复制应激后防止 MRE11 核酸酶降解新生 DNA 中的关键作用。在这里，我们展示了 SMARCAL1（一种 SNF2 家族 DNA 转位酶）的消耗，它可以重塑停滞的叉，恢复复制叉的稳定性并减少 BRCA1/2 缺陷细胞中复制应激诱导的 DNA 断裂和染色体畸变的形成。除 SMARCAL1 外，其他 SNF2 家族叉形重塑剂，包括 ZRANB3 和 HLTF，在复制应激时会导致 BRCA1/2 缺陷细胞中的新生 DNA 降解和基因组不稳定。我们的观察表明，BRCA1/2 缺陷细胞中新生的 DNA 降解是由于叉重塑器产生的反向叉的 MRE11 依赖性核水解处理的结果。这些研究为导致 BRCA1/2 缺陷细胞基因组不稳定的过程提供了机制见解。