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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 \u201cRAD51 paradox\u201d. 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.<\/jats:p>","DOI":"10.3390\/cells12081169","type":"journal-article","created":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T01:34:15Z","timestamp":1681695255000},"page":"1169","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Noncanonical Roles of RAD51"],"prefix":"10.3390","volume":"12","author":[{"given":"M\u00e9lissa","family":"Thomas","sequence":"first","affiliation":[{"name":"INSERM U1016, UMR 8104 CNRS, Institut Cochin, Universit\u00e9 de Paris Cit\u00e9, 24 rue du Faubourg St. Jacques, F-75014 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3674-5808","authenticated-orcid":false,"given":"Caroline","family":"Dubacq","sequence":"additional","affiliation":[{"name":"Institut de Biologie Paris Seine, IBPS, Neuroscience Paris Seine, NPS, INSERM, CNRS, Sorbonne Universit\u00e9, F-75005 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7889-1675","authenticated-orcid":false,"given":"Elise","family":"Rabut","sequence":"additional","affiliation":[{"name":"INSERM U1016, UMR 8104 CNRS, Institut Cochin, Universit\u00e9 de Paris Cit\u00e9, 24 rue du Faubourg St. Jacques, F-75014 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5088-0155","authenticated-orcid":false,"given":"Bernard S.","family":"Lopez","sequence":"additional","affiliation":[{"name":"INSERM U1016, UMR 8104 CNRS, Institut Cochin, Universit\u00e9 de Paris Cit\u00e9, 24 rue du Faubourg St. Jacques, F-75014 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9e","family":"Guirouilh-Barbat","sequence":"additional","affiliation":[{"name":"INSERM U1016, UMR 8104 CNRS, Institut Cochin, Universit\u00e9 de Paris Cit\u00e9, 24 rue du Faubourg St. Jacques, F-75014 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1038\/nrm2858","article-title":"Genomic instability\u2014An evolving hallmark of cancer","volume":"11","author":"Negrini","year":"2010","journal-title":"Nat. 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