TRPS1 drives heterochromatic origin refiring and cancer genome evolution

• Published in: Cell reports (Cambridge) 2021-03, Vol.34 (10), p.108814, Article 108814
• Main Authors: Yang, Jianguo, Liu, Xiaoping, Huang, Yunchao, He, Lin, Zhang, Wenting, Ren, Jie, Wang, Yue, Wu, Jiajing, Wu, Xiaodi, Shan, Lin, Yang, Xiaohan, Sun, Luyang, Liang, Jing, Zhang, Yu, Shang, Yongfeng
• Format: Article
• Language: English
• Subjects: Alcohol Oxidoreductases - antagonists & inhibitors; Alcohol Oxidoreductases - genetics; Alcohol Oxidoreductases - metabolism; Animals; breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; cancer genome evolution; Cell Line, Tumor; DNA Replication; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Evolution, Molecular; Female; H3K9me3; heterochromatic origin refiring; Heterochromatin - metabolism; Histones - metabolism; Humans; Mi-2 Nucleosome Remodeling and Deacetylase Complex - metabolism; Mice; Mice, SCID; Mutagenesis, Site-Directed; Protein Binding; Repressor Proteins - antagonists & inhibitors; Repressor Proteins - genetics; Repressor Proteins - metabolism; RNA Interference; RNA, Small Interfering - metabolism; therapeutic resistance; Transplantation, Heterologous; TRPS1
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.108814

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. [Display omitted] •TRPS1 interacts with replication machinery and binds to H3K9me3-marked origins•TRPS1 encourages chromatin loading of APC/C leading to uncontrolled origin refiring•TRPS mutations abolish TRPS1-promoted replication boosting and breast carcinogenesis•TRPS1 overexpression drives cancer genome evolution and therapeutic resistance The tricho-rhino-phalangeal syndrome-associated gene TRPS1 is also amplified in breast cancer. By leveraging the genetic mutations, Yang et al. identify an unexpected replication boosting role of TRPS1 for H3K9me3-marked heterochromatic origin activation, cancer genome evolution, and therapeutic resistance, thus revealing a critical aspect of TRPS1 in driving breast carcinogenesis through over-replication.