SPOP mutation induces replication over-firing by impairing Geminin ubiquitination and triggers replication catastrophe upon ATR inhibition

Jian Ma, Qing Shi, Gaofeng Cui, Haoyue Sheng, Maria Victoria Botuyan, Yingke Zhou, Yuqian Yan, Yundong He, Liguo Wang, Yuzhuo Wang, Georges Mer (), Dingwei Ye (), Chenji Wang () and Haojie Huang ()
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Jian Ma: Fudan University Shanghai Cancer Center
Qing Shi: Fudan University
Gaofeng Cui: Mayo Clinic College of Medicine and Science
Haoyue Sheng: Fudan University Shanghai Cancer Center
Maria Victoria Botuyan: Mayo Clinic College of Medicine and Science
Yingke Zhou: Mayo Clinic College of Medicine and Science
Yuqian Yan: Mayo Clinic College of Medicine and Science
Yundong He: Mayo Clinic College of Medicine and Science
Liguo Wang: Divison of Computational Biology, Mayo Clinic College of Medicine and Science
Yuzhuo Wang: BC Cancer Research Centre
Georges Mer: Mayo Clinic College of Medicine and Science
Dingwei Ye: Fudan University Shanghai Cancer Center
Chenji Wang: Fudan University
Haojie Huang: Mayo Clinic College of Medicine and Science

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-26049-6

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