BRCA1介导的DNA损伤修复通路与放化疗敏感性的研究

Genomic instability is a hallmark of cancer. Healthy cells maintain genomic integrity via DNA repair pathways to process DNA damage, and homologous recombination (HR) is the most high-fidelity DNA repair pathway. Mutations in DNA repair genes often occur in early onset of tumorigenesis, among them BRCA1 is one of the most famous tumor suppressor gene. For people carrying BRCA1 gene mutations, there is a high lifetime chance of developing multiple cancers. In the absence of BRCA1 activity, cells are incapable of repairing DNA breaks through the homologous recombination pathway (HR), instead, cells rely on other error-prone DNA repair pathways. The use of these pathways can lead to the formation of abnormal and potentially harmful chromosomal structures that promote tumorigenesis. Recent reports have demonstrated that it is possible to restore HR activity in BRCA1 deficient cells by deletion of the gene for the DNA damage response factor, 53BP1. These results suggest that in the setting of BRCA1 deficiency, 53BP1 may act as a molecular inhibitor of HR. Clinical evidence suggest that a subgroup of BRCA1 mutation carriers who are resistant to chemo- and radio-therapies expressing low level of 53BP1. The proposed research will explore the factors control the balance of HR and NHEJ in nasopharyngeal carcinoma, a type of cancer with hypersensitivity to radiotherapy. The interplay between 53BP1 network and BRCA1 will be further characterized to refine our understanding of the underlying mechanism, as well as an attempt to identify other mysterious genes work with BRCA and other HR-antagonizing genes, which may be informative to sensitizing radiotherapy. A fuller understanding of this phenomenon will lead to personalized therapies to reduce the lifetime risk of tumor formation in HR-deficient carriers.

基因组不稳定性是肿瘤的标志性特征。正常细胞通过精确修复DNA损伤处来保证基因组的完整性，其中最保真的修复方式是同源重组（HR）。肿瘤发生早期经常伴随着DNA损伤修复基因的突变，而BRCA1就是其中最著名的抑癌基因。携带BRCA1突变基因的一生中有极大的概率会罹患肿瘤。在BRCA1突变的病人体内HR失活，另一种易出错的修复方式，称之为非同源性末端连接(NHEJ) 成为主导通路，这种易错的修复方式会产生有害的染色体结构而促使肿瘤发生。近年来发现53BP1，一个促进NHEJ的DNA修复基因可以拮抗BRCA1介导的HR修复。临床研究发现部分BRCA1缺陷的病人丢失了53BP1的表达从而产生对放化疗的抗性。本项目将以对放疗敏感的鼻咽癌为模型，进一步揭示体内制约HR和NHEJ的机制，发现BRCA1以外的HR基因和53BP1复合物以外的HR拮抗分子，从而设计个体化治疗测率以降低HR缺陷患者罹患肿瘤的风险

鼻咽癌是头颈部肿瘤中对放射线最敏感的肿瘤。本项目拟针对鼻咽癌特有的放化疗敏感现象，深入研究敏感性背后的分子基础，阐明EB病毒和宿主遗传学在疾病发生发展和放化疗中的作用，从EB病毒感染的角度开发鼻咽癌放疗增敏药物和新型化疗药物，取得以下成果：1. 揭示遗传因素和EB病毒在鼻咽癌中的作用。发现鼻咽癌易感基因通过抑制TGFb信号通路实现EB病毒稳定感染和细胞去分化（2018 Cancer Res），以及上皮细胞抗EBV的防御机制（2018 PloS Pathog）。2. 开发鼻咽癌放疗增敏剂和新型化疗药物。包括利用EBV改变宿主表观遗传学筛选到放疗增敏药物JQ1（2018 Cell Death & Dis）；通过诱导分化治疗鼻咽癌（2018 Theronostics，2019 Cell Death & Dis）；破坏血管拟态以促进病毒裂解和肿瘤消退（2018 Nat Commun，2018 Cancer Sci）。本项目探索了鼻咽癌的新型靶向放化疗方案，对鼻咽癌的病因和治疗做出了贡献。项目执行期内共发表相关7篇SCI论文，总影响因子54分，总被引92次。获批鼻咽癌新型治疗专利一项。负责人于2019年获得国自然优秀青年基金的资助。