TRPS1 drives heterochromatic origin refiring and cancer genome evolution

• DOI: 10.1016/j.celrep.2021.108814
• Publication Date: 2021-03-10T01:57:35Z
• 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
• Keywords: therapeutic resistance; DNA Replication; 0301 basic medicine; QH301-705.5; Transplantation, Heterologous; Breast Neoplasms; Mice, SCID; H3K9me3; Evolution, Molecular; Histones; Mice; 03 medical and health sciences; breast cancer; TRPS1; Cell Line, Tumor; Heterochromatin; Animals; Humans; Biology (General); RNA, Small Interfering; 0303 health sciences; 3. Good health; DNA-Binding Proteins; Repressor Proteins; Alcohol Oxidoreductases; Mutagenesis, Site-Directed; heterochromatic origin refiring; Female; RNA Interference; cancer genome evolution; Mi-2 Nucleosome Remodeling and Deacetylase Complex; Protein Binding

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.