RAD51 paralog gene mutations are observed in both hereditary breast and ovarian cancers. Classically, defects in RAD51 paralog function are associated with homologous recombination (HR) deficiency and increased genomic instability. Several recent investigative advances have enabled characterization of non-canonical RAD51 paralog function during DNA replication. Here we discuss the role of the RAD51 paralogs and their associated complexes in integrating a robust response to DNA replication stress. We highlight recent discoveries suggesting that the RAD51 paralogs complexes mediate lesion-specific tolerance of replicative stress following exposure to alkylating agents and the requirement for the Shu complex in fork restart upon fork stalling by dNTP depletion. In addition, we describe the role of the BCDX2 complex in restraining and promoting fork remodeling in response to fluctuating dNTP pools. Finally, we highlight recent work demonstrating a requirement for RAD51C in recognizing and tolerating methyl-adducts. In each scenario, RAD51 paralog complexes play a central role in lesion recognition and bypass in a replicative context. Future studies will determine how these critical functions for RAD51 paralog complexes contribute to tumorigenesis.

RAD51在遗传性乳腺癌和卵巢癌中均观察到旁系同源基因突变。传统上，RAD51 旁系同源基因功能缺陷与同源重组 (HR) 缺陷和基因组不稳定性增加有关。最近的几项研究进展已经能够表征 DNA 复制过程中的非规范 RAD51 旁系同源函数。在这里，我们讨论了 RAD51 旁系同源物及其相关复合物在整合对 DNA 复制压力的强烈反应中的作用。我们强调了最近的发现，表明 RAD51 旁系同源物复合物介导了暴露于烷化剂后对复制应激的病变特异性耐受性，以及在 dNTP 耗尽导致叉子停滞时叉子重新启动时对 Shu 复合物的要求。此外，我们描述了 BCDX2 复合体在抑制和促进叉重塑以响应波动的 dNTP 池中的作用。最后，我们强调了最近的工作，证明了 RAD51C 在识别和耐受甲基加合物方面的要求。在每种情况下，RAD51 paralog 复合体在复制环境中的病变识别和旁路中起着核心作用。未来的研究将确定 RAD51 旁系同源复合物的这些关键功能如何促进肿瘤发生。