Watson Alizhah J, Shaffer Michaela L, Bouley Renee A, Petreaca Ruben C
Biology Program, The Ohio State University, Marion, OH 433023, USA.
Department of Chemistry and Biochemistry, The Ohio State University, Marion, OH 43302, USA.
Cancers (Basel). 2023 Sep 6;15(18):4439. doi: 10.3390/cancers15184439.
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）是在S期或有丝分裂期间挽救停滞的复制叉或修复DNA双链断裂（DSB）的主要机制。在人类细胞中，BRCA2-BRCA1-PALB2模块促进了同源重组，该模块将RAD51重组酶加载到切除的单链DNA末端以启动修复。尽管该过程对于无差错修复至关重要，但不受限制的同源重组会导致染色体重排和基因组不稳定。F-box DNA解旋酶1（FBH1）拮抗BRCA2-BRCA1-PALB2的作用，以限制过度重组并防止基因组不稳定。在这里，我们使用癌症体细胞突变目录（COSMIC）分析了癌细胞中报道的FBH1突变，以了解它们如何与BRCA2-BRCA1-PALB2相互作用。与酵母先前的结果一致，我们发现FBH1突变与BRCA2突变同时发生，在某种程度上也与BRCA1和PALB2同时发生。我们还描述了一些与RAD52同时发生的突变，RAD52是辅助RAD51加载器和单链退火促进剂，独立于RAD51。通过计算机模拟研究了关键FBH1突变对蛋白质功能的作用，发现Q650K突变会破坏蛋白质结构。综上所述，这项工作突出了几个DNA损伤修复基因中的突变如何促进细胞转化和永生化。
