TRPS1 drives heterochromatic origin refiring and cancer genome evolution

• Main Authors: Jianguo Yang, Xiaoping Liu, Yunchao Huang, Lin He, Wenting Zhang, Jie Ren, Yue Wang, Jiajing Wu, Xiaodi Wu, Lin Shan, Xiaohan Yang, Luyang Sun, Jing Liang, Yu Zhang, Yongfeng Shang
• Format: Article
• Language: English
• Published: Elsevier 2021-03-01
• Series: Cell Reports
• Subjects: heterochromatic origin refiring; TRPS1; H3K9me3; breast cancer; cancer genome evolution; therapeutic resistance
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124721001285

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.