The tumor suppressor menin is a key scaffold mediator for homologous recombination repair
TL;DR
It is reported that the scaffold protein menin, encoded by the Men1 gene, plays a crucial bridging role in H3K36-mediated HR repair, validating that menin governs HR repair in an H3K36me3-dependent manner.
Abstract
Abstract SETD2-mediated H3K36me3 reprogramming is involved in homologous recombination (HR) repair; however, the dynamics of this repair process remain unclear. Here, we report that the scaffold protein menin, encoded by the Men1 gene, plays a crucial bridging role in H3K36-mediated HR repair. Genetic ablation of Men1 resulted in spontaneous lung carcinogenesis and was accompanied by severe genomic instability. Mechanistically, menin directly recognizes histone H2A.X via its Val371–Gln400 motif, and DNA damage markedly promotes the specific interaction between menin and γH2A.X. Subsequently, SETD2 is recruited to DNA damage sites by menin and acts as a writer to catalyze H3K36me3 reprogramming at local chromatin. LEDGF, as a reader, recognizes the H3K36me3 marker and further recruits CtIP as an effector to perform DNA end resection, ultimately activating the RPA2/Rad51 pathway. Restoring H3K36me3 via pharmacological intervention rescued impaired HR repair in Men1-deficient cells, further validating that menin governs HR repair in an H3K36me3-dependent manner. The results of the present study provide the detailed molecular mechanism underlying the previously described functions of H3K36me3 remodeling in HR repair.