Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Health Science Center, Beijing 100191, China.
Department of Biochemistry and Molecular Biology, School of Medicine, Hangzhou Normal University, Hangzhou 311121, China; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China.
Cell Rep. 2021 Mar 9;34(10):108814. 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.
利用自然发生的基因突变可以帮助我们发现已确立的癌症基因的新方面。我们在这里报告，TRPS1 是与毛发-鼻-指综合征 (TRPS) 相关的基因，最近被确定为潜在的乳腺癌驱动基因，它通过调节复制促进乳腺癌发生。TRPS1 景观的表观基因组分解表明，近一半的 H3K9me3 标记的异染色质起始点被 TRPS1 占据，在那里它促进 APC/C 的染色质加载，导致不受控制的起始点重新点火。TRPS1 通过其 GATA 和 IKAROS 结构域对 H3K9me3 的非典型读取与基因组结合，而 TRPS 相关突变会影响其染色质结合、复制增强和致瘤性。一致地，过表达野生型 TRPS1 但不是与 TRPS 相关的突变体足以驱动癌症基因组扩增，这些扩增经历了一种染色体外途径，并动态进化以赋予治疗耐药性。总之，这些结果揭示了 TRPS1 在驱动异染色质起始点火和乳腺癌基因组进化中的关键功能。
