Homologous recombination (HR) is the major mechanism of rescue of stalled replication forks or repair of DNA double-strand breaks (DSBs) during S phase or mitosis. In human cells, HR is facilitated by the BRCA2-BRCA1-PALB2 module, which loads the RAD51 recombinase onto a resected single-stranded DNA end to initiate repair. Although the process is essential for error-free repair, unrestrained HR can cause chromosomal rearrangements and genome instability. F-box DNA Helicase 1 (FBH1) antagonizes the role of BRCA2-BRCA1-PALB2 to restrict hyper-recombination and prevent genome instability. Here, we analyzed reported FBH1 mutations in cancer cells using the Catalogue of Somatic Mutations in Cancers (COSMIC) to understand how they interact with the BRCA2-BRCA1-PALB2. Consistent with previous results from yeast, we find that FBH1 mutations co-occur with BRCA2 mutations and to some degree BRCA1 and PALB2. We also describe some co-occurring mutations with RAD52, the accessory RAD51 loader and facilitator of single-strand annealing, which is independent of RAD51. In silico modeling was used to investigate the role of key FBH1 mutations on protein function, and a Q650K mutation was found to destabilize the protein structure. Taken together, this work highlights how mutations in several DNA damage repair genes contribute to cellular transformation and immortalization.
同源重组（HR）是细胞在S期或有丝分裂过程中修复停滞复制叉或DNA双链断裂（DSB）的主要机制。在人类细胞中，BRCA2-BRCA1-PALB2复合模块通过将RAD51重组酶装载到经过末端切除的单链DNA上以启动修复过程，从而促进同源重组。尽管该过程对实现无差错修复至关重要，但不受调控的同源重组可能导致染色体重排和基因组不稳定性。F-box DNA解旋酶1（FBH1）通过拮抗BRCA2-BRCA1-PALB2复合模块的功能来限制过度重组，从而维持基因组稳定性。本研究利用癌症体细胞突变目录（COSMIC）数据库，系统分析了癌细胞中已报道的FBH1突变，以探究其与BRCA2-BRCA1-PALB2复合模块的相互作用机制。与既往酵母研究结果一致，我们发现FBH1突变与BRCA2突变存在共现现象，且在一定程度上与BRCA1及PALB2突变共现。同时，我们还观察到FBH1与RAD52（作为RAD51的辅助装载因子及不依赖RAD51的单链退火修复促进因子）存在部分共现突变。通过计算机模拟分析关键FBH1突变对蛋白质功能的影响，发现Q650K突变会导致蛋白质结构失稳。综上所述，本研究揭示了多个DNA损伤修复基因的突变如何协同促进细胞转化与永生化过程。
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