TRPS1 drives heterochromatic origin refiring and cancer genome evolution

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
DOI: 10.1016/j.celrep.2021.108814 Publication Date: 2021-03-10T01:57:35Z
ABSTRACT
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.
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