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| Status |
Public on Aug 08, 2022 |
| Title |
TRPS1 drives heterochromatic origin refiring and cancer genome evolution [copy number] |
| Organism |
Homo sapiens |
| Experiment type |
Genome variation profiling by SNP array
SNP genotyping by SNP array
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| Summary |
The molecular etiology underlying TRPS1 loss-of-function in tricho-rhino-phalangeal syndrome (TRPS) remains to be understood. Intriguingly, TRPS1 is also bioinformatically postulated as a breast cancer driver. We report here that TRPS1 is prevalently amplified in breast cancer and promotes breast carcinogenesis. We showed that the tumorigenic potential of TRPS1 is derived from its nucleation of the replication machinery and its enforced replication of H3K9me3-marked heterochromatic regions. During early stage of genome duplication, TRPS1 encourages chromatin loading of the anaphase-promoting complex (APC/C) and subsequent degradation of Geminin, an inhibitor for the assembly of the pre-replication complex, leading to uncontrolled refiring of the heterochromatic replication origins. Overexpression of wild-type but not TRPS-associated loss-of-function mutants of TRPS1 is sufficient to drive genome amplification that mimics the genomic alterations in cancer, and TRPS1-evoked aberrant genome dynamically evolves to confer therapeutic resistance to a broad spectrum of treatment compounds. Together, these results link TRPS1 to heterochromatin replication, highlighting the sufficiency of a single oncogene to drive cancer genome evolution.
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| Overall design |
We established TRPS1-overexpressed cell lines and extracted genomic DNA in control or TRPS1 overexpressed cells, and examined the copy number alterations in control and TRPS1 cells
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| Contributor(s) |
Yang J, Zhang Y |
| Citation(s) |
33691114 |
| Submission date |
Aug 08, 2019 |
| Last update date |
Nov 08, 2022 |
| Contact name |
Yu Zhang |
| Organization name |
Peking University Health Science Center
|
| Street address |
Xueyuan Road
|
| City |
Beijing |
| ZIP/Postal code |
100191 |
| Country |
China |
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| Platforms (1) |
| GPL6801 |
[GenomeWideSNP_6] Affymetrix Genome-Wide Human SNP 6.0 Array |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA559389 |
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