BRCA2基因新突变导致的甲基缺失引起高危家族卵巢/乳腺癌发生的机制研究

批准号:
81972444
项目类别:
面上项目
资助金额:
55.0 万元
负责人:
季韶洋
依托单位:
学科分类:
肿瘤遗传与进化
结题年份:
2023
批准年份:
2019
项目状态:
已结题
项目参与者:
季韶洋
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中文摘要
抑癌基因BRCA2对于细胞应对DNA双链断裂损伤不可或缺。其蛋白通过招募修复因子、激活同源DNA配对支持损伤位点同源重组修复(HR)。BRCA2突变可导致基因组不稳定和家族遗传性卵巢/乳腺癌高发。本项目前期应用全外显子测序在癌症高危家族中发现了一个新的BRCA2异亮氨酸>甲硫氨酸胚系突变。根据前期研究,提出科学假说:BRCA2特异位点的异亮氨酸侧链甲基是一个固有的甲基“信号”,它的缺失导致修复相关蛋白招募受损,ssDNA检索同源dsDNA、D-环形成过程受到抑制,造成HR受阻。本课题利用点突变、CRISPR/Cas9、DNA单链交换分析、CoIP等方法在细胞系、原代细胞和小鼠模型进行此突变抑制HR过程的细胞学评价和体内外机制研究。从临床样本、细胞功能、生化分子机制和小鼠模型四个层次阐明此BRCA2突变的甲基效应,为BRCA2蛋白的固有甲基“信号”理论提供实验证据以及癌症的诊治提供新靶点。
英文摘要
The tumor suppressor gene BRCA2 is indispensable for cells to cope with DNA double-strand breaks. BRCA2 participates in key HR processes by recruiting repair proteins, activating homologous DNA sequence pairing and exchanging. Mutations in BRCA2 can result in impaired genomic stability and a high incidence of familial ovarian/breast cancer.Using the whole-exome sequencing, we found one novel BRCA2 germline mutation (I>M) in the high-risk family of ovarian/breast cancer, which is significantly associated with the high incidence of cancer in this family. According to the previous study, the scientific hypothesis is proposed: the branched methyl group of isoleucine at the key site of BRCA2 is an intrinsic methyl "signal", and its deletion leads to the damaged recruitment of repair-related proteins, and/or inhibition of single-strand DNA retrieval of genetic information from homologous double-strand DNA, and the HR critical steps blocked. In this study, we use site mutation, CRISPR/Cas9, DNA single-strand exchange analysis, co-immunoprecipitation to evaluate the inhibition of HR, cell function and the molecular mechanism in cell lines, primary cells and mouse models. We elucidate the methyl effect and mechanism of BRCA2 point mutation from four diractions: clinical samples, cell function,biochemical molecular mechanism and mouse models. We provide experimental evidence for the inherent methyl "signal" theory of BRCA2 protein and provide new targets for cancer diagnosis and treatment.
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DOI:10.3390/ijms25021160
发表时间:2024-01-18
期刊:International journal of molecular sciences
影响因子:5.6
作者:
通讯作者:
DOI:10.19852/j.cnki.jtcm.20220617.004
发表时间:2022
期刊:Journal of Traditional Chinese Medicine
影响因子:2.6
作者:Zhang Liang;Han Qian;Yi Yanxiao;Ji Shaoyang;Xin Mingwei
通讯作者:Xin Mingwei
DOI:10.1186/s12951-022-01763-5
发表时间:2023-01-05
期刊:JOURNAL OF NANOBIOTECHNOLOGY
影响因子:10.2
作者:Wu, Guanghao;Su, Qihang;Li, Jie;Xue, Chao;Zhu, Jie;Cai, Qiuchen;Huang, Jingbiao;Ji, Shaoyang;Cheng, Biao;Ge, Hengan
通讯作者:Ge, Hengan
DOI:10.3390/vaccines8030351
发表时间:2020-07-01
期刊:Vaccines
影响因子:7.8
作者:Liu DQ;Lu S;Zhang L;Huang YR;Ji M;Sun XY;Liu XG;Liu RT
通讯作者:Liu RT
基于PEG-长链脂肪烷修饰的人生长激素长效剂型
- 批准号:81402861
- 项目类别:青年科学基金项目
- 资助金额:23.0万元
- 批准年份:2014
- 负责人:季韶洋
- 依托单位:
国内基金
海外基金
