TRPS1 drives heterochromatic origin refiring and cancer genome evolution

Cell Reports

Jiajing Wu¹  Xiaodi Wu²  Lin Shan²  Xiaohan Yang²  Jianguo Yang³  Lin He³  Yu Zhang³  Wenting Zhang³  Xiaoping Liu³  Yongfeng Shang³  Yunchao Huang³  Jie Ren³  Luyang Sun³  Jing Liang³  Yue Wang⁴ 

[1] Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China;Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China;Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Health Science Center, Beijing 100191, China;Department of Biochemistry and Molecular Biology, School of Medicine, Hangzhou Normal University, Hangzhou 311121, China;

关键词: heterochromatic origin refiring;    TRPS1;    H3K9me3;    breast cancer;    cancer genome evolution;    therapeutic resistance;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: Exploitation of naturally occurring genetic mutations could empower the discovery of novel aspects of established cancer genes. We report here that TRPS1, a gene linked to the tricho-rhino-phalangeal syndrome (TRPS) and recently identified as a potential breast cancer driver, promotes breast carcinogenesis through regulating replication. Epigenomic decomposition of TRPS1 landscape reveals nearly half of H3K9me3-marked heterochromatic origins are occupied by TRPS1, where it encourages the chromatin loading of APC/C, resulting in uncontrolled origin refiring. TRPS1 binds to the genome through its atypical H3K9me3 reading via GATA and IKAROS domains, while TRPS-related mutations affect its chromatin binding, replication boosting, and tumorigenicity. Concordantly, overexpression of wild-type but not TRPS-associated mutants of TRPS1 is sufficient to drive cancer genome amplifications, which experience an extrachromosomal route and dynamically evolve to confer therapeutic resistance. Together, these results uncover a critical function of TRPS1 in driving heterochromatin origin firing and breast cancer genome evolution.

【 授权许可】

Unknown