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