Replication repriming by the specialized primase-polymerase PRIMPOL ensures the continuity of DNA synthesis during replication stress. PRIMPOL activity generates residual post-replicative single-stranded nascent DNA gaps, which are linked with mutagenesis and chemosensitivity in BRCA1/2-deficient models, and which are suppressed by replication fork reversal mediated by the DNA translocases SMARCAL1 and ZRANB3. Here, we report that the MRE11 regulator MRNIP limits the prevalence of PRIMPOL and MRE11-dependent ssDNA gaps in cells in which fork reversal is perturbed either by treatment with the PARP inhibitor Olaparib, or by depletion of SMARCAL1 or ZRANB3. MRNIP-deficient cells are sensitive to PARP inhibition and accumulate PRIMPOL-dependent DNA damage, supportive of a pro-survival role for MRNIP linked to the regulation of gap prevalence. In MRNIP-deficient cells, post-replicative gap filling is driven in S-phase by UBC13-mediated template switching involving REV1 and the TLS polymerase Pol-ζ. Our findings represent the first report of modulation of post-replicative ssDNA gap dynamics by a direct MRE11 regulator.

中文翻译：

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MRNIP 限制复制压力期间的 ssDNA 间隙


由专门的引物酶聚合酶 PRIMPOL 进行的复制重新启动可确保复制应激期间 DNA 合成的连续性。 PRIMPOL 活性产生残留的复制后单链新生 DNA 间隙，这些间隙与 BRCA1/2 缺陷模型中的诱变和化学敏感性有关，并受到 DNA 易位酶 SMARCAL1 和 ZRANB3 介导的复制叉逆转的抑制。在这里，我们报告说，MRE11 调节剂 MRNIP 限制了细胞中 PRIMPOL 和 MRE11 依赖性 ssDNA 缺口的流行，在这些细胞中，通过 PARP 抑制剂 Olaparib 治疗或通过 SMARCAL1 或 ZRANB3 的消耗来扰乱叉逆转。 MRNIP 缺陷细胞对 PARP 抑制敏感，并积累 PRIMPOL 依赖性 DNA 损伤，支持 MRNIP 与间隙流行调节相关的促生存作用。在 MRNIP 缺陷细胞中，S 期复制后间隙填充由 UBC13 介导的涉及 REV1 和 TLS 聚合酶 Pol-ze 的模板转换驱动。我们的研究结果代表了直接 MRE11 调节剂调节复制后 ssDNA 间隙动态的第一份报告。