INSERM U1016, UMR 8104 CNRS, Institut Cochin, Université de Paris Cité, 24 rue du Faubourg St. Jacques, F-75014 Paris, France.
Institut de Biologie Paris Seine, IBPS, Neuroscience Paris Seine, NPS, INSERM, CNRS, Sorbonne Université, F-75005 Paris, France.
Cells. 2023 Apr 15;12(8):1169. doi: 10.3390/cells12081169.
Homologous recombination (HR), an evolutionary conserved pathway, plays a paramount role(s) in genome plasticity. The pivotal HR step is the strand invasion/exchange of double-stranded DNA by a homologous single-stranded DNA (ssDNA) covered by RAD51. Thus, RAD51 plays a prime role in HR through this canonical catalytic strand invasion/exchange activity. The mutations in many HR genes cause oncogenesis. Surprisingly, despite its central role in HR, the invalidation of RAD51 is not classified as being cancer prone, constituting the "RAD51 paradox". This suggests that RAD51 exercises other noncanonical roles that are independent of its catalytic strand invasion/exchange function. For example, the binding of RAD51 on ssDNA prevents nonconservative mutagenic DNA repair, which is independent of its strand exchange activity but relies on its ssDNA occupancy. At the arrested replication forks, RAD51 plays several noncanonical roles in the formation, protection, and management of fork reversal, allowing for the resumption of replication. RAD51 also exhibits noncanonical roles in RNA-mediated processes. Finally, RAD51 pathogenic variants have been described in the congenital mirror movement syndrome, revealing an unexpected role in brain development. In this review, we present and discuss the different noncanonical roles of RAD51, whose presence does not automatically result in an HR event, revealing the multiple faces of this prominent actor in genomic plasticity.
同源重组（HR）是一种进化上保守的途径，在基因组可塑性中起着至关重要的作用。HR 的关键步骤是 RAD51 覆盖的双链 DNA 的单链侵入/交换。因此，RAD51 通过这种典型的催化链侵入/交换活性在 HR 中起着主要作用。许多 HR 基因的突变导致肿瘤发生。令人惊讶的是，尽管 RAD51 在 HR 中起着核心作用，但 RAD51 的失活并未被归类为易患癌症，这构成了“RAD51 悖论”。这表明 RAD51 发挥了其他非典型作用，这些作用独立于其催化链侵入/交换功能。例如，RAD51 与 ssDNA 的结合可以防止非保守的致突变性 DNA 修复，这与它的链交换活性无关，但依赖于其 ssDNA 占有率。在停滞的复制叉处，RAD51 在叉反转的形成、保护和管理中发挥多种非典型作用，从而允许复制的恢复。RAD51 还在 RNA 介导的过程中发挥非典型作用。最后，在先天性镜像运动综合征中描述了 RAD51 的致病性变体，揭示了其在大脑发育中的意外作用。在这篇综述中，我们提出并讨论了 RAD51 的不同非典型作用，其存在并不自动导致 HR 事件，揭示了这个在基因组可塑性中突出的角色的多面性。
