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

ABSTRACT: Geminin ubiquitin modification site mapping, Geminin coIP-mass spec

ORGANISM(S): Homo Sapiens

SUBMITTER: Jian Ma

PROVIDER: PXD027915 | iProX | Thu Aug 12 00:00:00 BST 2021

REPOSITORIES: iProX

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

Ma Jian J Shi Qing Q Cui Gaofeng G Sheng Haoyue H Botuyan Maria Victoria MV Zhou Yingke Y Yan Yuqian Y He Yundong Y Wang Liguo L Wang Yuzhuo Y Mer Georges G Ye Dingwei D Wang Chenji C Huang Haojie H

Nature communications 20211001 1

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 requi ...[more]

PMID: 34599168

Similar Datasets

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

Project description: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.

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Inhibition of Ubc13-mediated ubiquitination by GPS2 regulates multiple stages of B cell development

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USP7 inhibition induces apoptosis in glioblastoma by enhancing ubiquitination of ARF4.

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Gene expression in human endometrial cancer tissues and serous papillary endometrial cancer cell line, SPAC-1L, treated by STAT1-siRNA and/or IFN-gamma

Project description:Endometrial cancer is one of the most common gynecologic malignancies, and patients with high grade disease, especially serous papillary subtype (SPEC) are often related to the poor outcomes. Recent genome-wide analyses have revealed that SPEC exhibits gene expression profiles that are distinct from the endometrioid histologic subtype; therefore, it is important to identify the SPEC driver genes or pathways responsible for the inherently aggressive phenotypes and to develop SPEC-specific therapies to target these driver genes or pathways. Through array-based analysis and immunohistochemical staining of human endometrial cancer tissue, STAT1 is identified high expressed, and can distinguish SPEC from other subtypes of endometrial cancer. In vitro and in vivo experiments show STAT1 role as a pro-survival factor in SPEC. STAT1 was identified as a master gene modulating “transcriptional pro-survival pathways” to enhance multiple malignant characteristics These finding may suggest that targeting of STAT1, the SPEC driver gene, may provide the means to improve poor outcomes for patients with SPEC. We used microarrays to clarify the changes of gene expression along with STAT1-siRNA treatment and to confirm whether there are any changes on genes expression related to STAT1 pathway. We also used the microarray data to clarify genes signatures which can distinguish subtype of human endometrial cancers.

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