Nuclear lamins are type V intermediate filament proteins. Lamins, including LA, LB1, LB2, and LC, are the major protein components forming the nuclear lamina to support the mechanical stability of the mammalian cell nucleus. Increasing evidence has shown that LA participates in homologous recombination (HR) repair of DNA double-strand breaks (DSBs) . However, the mechanisms underlying this process are incompletely understood. We recently identified the first lamin-binding ligand 1 (LBL1) that directly binds LA and inhibited cancer cell growth. We provided here further mechanistic investigations of LBL1 and revealed that LA interacts with the HR recombinase Rad51 to protect Rad51 from degradation. LBL1 inhibits LA–Rad51 interaction leading to accelerated proteasome-mediated degradation of Rad51, culminating in inhibition of HR repair of DSBs. These results uncover a novel post-translational regulation of Rad51 by LA and suggest that targeting the LA–Rad51 axis may represent a promising strategy to develop cancer therapeutics.

中文翻译：

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层粘连蛋白配体抑制DNA双链断裂的同源重组修复。

核纤层蛋白是V型中间丝蛋白。包括LA，LB1，LB2和LC在内的核纤层蛋白是形成核层以支持哺乳动物细胞核机械稳定性的主要蛋白质成分。越来越多的证据表明，LA参与DNA双链断裂（DSB）的同源重组（HR）修复。但是，此过程的机制尚不完全清楚。我们最近确定了第一个直接与LA结合并抑制癌细胞生长的Lamin结合配体1（LBL1）。我们在这里提供了LBL1的进一步机理研究，并揭示了LA与HR重组酶Rad51相互作用以保护Rad51免受降解。LBL1抑制LA–Rad51相互作用，导致蛋白酶体介导的Rad51加速降解，最终抑制HR对DSB的修复。这些结果揭示了LA对Rad51的新的翻译后调控，并表明靶向LA–Rad51轴可能代表了开发癌症治疗剂的有前途的策略。