期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-26049-6
关键词
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资金
- Mayo Clinic Foundation
- Mayo Clinic Center for Biomedical Discovery [098]
- National Institutes of Health [R01 CA132878]
- National Natural Science Foundation of China [81672558, 81201533, 81972396, 81672544, 81872099]
- U.S. Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357]
The study reveals that the CULLIN3 E3 ubiquitin ligase adaptor protein SPOP plays a crucial role in preventing DNA replication over-firing and genome instability by affecting Geminin ubiquitination. Mutations in SPOP may lead to replication origin over-firing, replication stress, and cell death, suggesting potential susceptibility to ATR inhibitor therapy in SPOP-mutated tumors.
Geminin and its binding partner Cdt1 are essential for the regulation of DNA replication. Here we show that the CULLIN3 E3 ubiquitin ligase adaptor protein SPOP binds Geminin at endogenous level and regulates DNA replication. SPOP promotes K27-linked non-degradative poly-ubiquitination of Geminin at lysine residues 100 and 127. This poly-ubiquitination of Geminin prevents DNA replication over-firing by indirectly blocking the association of Cdt1 with the MCM protein complex, an interaction required for DNA unwinding and replication. SPOP is frequently mutated in certain human cancer types and implicated in tumorigenesis. We show that cancer-associated SPOP mutations impair Geminin K27-linked poly-ubiquitination and induce replication origin over-firing and re-replication. The replication stress caused by SPOP mutations triggers replication catastrophe and cell death upon ATR inhibition. Our results reveal a tumor suppressor role of SPOP in preventing DNA replication over-firing and genome instability and suggest that SPOP-mutated tumors may be susceptible to ATR inhibitor therapy. Geminin-Cdt1 plays essential roles in the regulation of DNA replication. Here the authors reveal that the CULLIN3 E3 ubiquitin ligase adaptor protein SPOP prevents DNA replication over-firing and genome instability by affecting Geminin ubiquitination.
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