Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
Indian Institute of Science Education and Research, Tirupati, India.
Int J Biochem Cell Biol. 2019 Feb;107:128-139. doi: 10.1016/j.biocel.2018.12.013. Epub 2018 Dec 24.
Cancer cells exhibit HR defects, increased proliferation and checkpoint aberrations. Tumour suppressor proteins, BRCA2 and p53 counteract such aberrant proliferation by checkpoint regulation. Intriguingly, chemo-resistant cancer cells, exhibiting mutated BRCA2 and p53 protein survive even with increased DNA damage accumulation. Such cancer cells show upregulation of RAD52 tumour suppressor protein implying that RAD52 might be providing survival advantage to cancer cells. To understand this paradoxical condition of a tumour suppressor protein facilitating cancer cell survival, in the current study, we investigate the role of RAD52 overexpression in BRCA2 deficient cells. We provide evidence that RAD52 protein alleviates HR inhibition imposed by p53 in BRCA2 deficient cells. In addition, we study the role of RAD52 protein during short replication stress in BRCA2 deficient cells. BRCA2 deficient cells exhibit excessive origin firing and checkpoint evasion in the presence of prevailing DNA damage. Interestingly, overexpression of RAD52 rescues the excessive origin firing and checkpoint defects observed in BRCA2 deficient cells, indicating RAD52 protein compensates for the loss of BRCA2 function. We show that RAD52 protein, just as BRCA2, interacts with pCHK1 checkpoint protein and helps maintain the checkpoint control in BRCA2 deficient cells during DNA damage response.
癌细胞表现出 HR 缺陷、增殖增加和检查点异常。肿瘤抑制蛋白 BRCA2 和 p53 通过检查点调节来对抗这种异常增殖。有趣的是，即使 DNA 损伤积累增加，具有突变 BRCA2 和 p53 蛋白的化疗耐药癌细胞也能存活。这些癌细胞中 RAD52 肿瘤抑制蛋白上调，表明 RAD52 可能为癌细胞提供生存优势。为了理解肿瘤抑制蛋白促进癌细胞存活的这种自相矛盾的情况，在本研究中，我们研究了 RAD52 过表达在 BRCA2 缺陷细胞中的作用。我们提供的证据表明，RAD52 蛋白减轻了 BRCA2 缺陷细胞中 p53 对 HR 的抑制作用。此外，我们研究了 RAD52 蛋白在 BRCA2 缺陷细胞中短暂复制应激期间的作用。在存在流行的 DNA 损伤的情况下，BRCA2 缺陷细胞表现出过度的起始点火和检查点逃逸。有趣的是，RAD52 蛋白的过表达挽救了在 BRCA2 缺陷细胞中观察到的过度起始点火和检查点缺陷，表明 RAD52 蛋白补偿了 BRCA2 功能的丧失。我们表明，RAD52 蛋白与 pCHK1 检查点蛋白相互作用，就像 BRCA2 一样，有助于在 DNA 损伤反应期间维持 BRCA2 缺陷细胞中的检查点控制。
