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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,8,18]]},"abstract":"<jats:p>DNA double-strand breaks, including those arising from DNA interstrand crosslinks, are highly cytotoxic forms of DNA damage. Their precise repair by homologous recombination (HR) is essential for maintaining genomic stability. During HR, timely disassembly of the core machinery, RAD51 nucleoprotein filaments, is critical. The FIGNL1\u2013FIRRM (also known as C1orf112) AAA+ ATPase has recently been identified by us and others as a novel anti-recombinase that facilitates RAD51 disassembly via an ATPase-driven unfolding mechanism distinct from all previously characterized pathways. In this study, we identify MACIR\/C5orf30 as an adaptor for FIGNL1\u2013FIRRM unfoldase. MACIR directly binds FIRRM, forming a ternary complex that promotes RAD51 filament disassembly and facilitates repair of DNA damage induced by agents including aldehydes and platinum drugs. MACIR loss leads to DNA damage accumulation and genome instability, activates inflammatory signaling, linking MACIR deficiency to autoimmune and tumor-related pathologies. We further show that MACIR\u2019s direct interactions with FIRRM and DNA are both required for DNA repair, indicating that MACIR functionally links these components. High expression of MACIR\u2013FIRRM\u2013FIGNL1 correlates with poor prognosis in ovarian cancer patients, and pharmacological targeting of this complex with the inhibitors (small-molecule compound 8 and 10) we identified sensitizes ovarian cancer cells to platinum drugs. Therefore, our findings reveal MACIR as a critical regulatory adaptor within this RAD51-unfolding complex, which functions in an additional layer of control over DNA repair and genome stability, and suggest that its inhibition could enhance chemotherapeutic efficacy in cancer treatment.<\/jats:p>","DOI":"10.1073\/pnas.2531632123","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T18:33:32Z","timestamp":1786646012000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1,"title":["A regulatory adaptor for RAD51\u2019s AAA+ unfoldase promotes homologous recombination\u2013mediated DNA repair and genome 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