SPOP mutation induces replication over-firing by impairing Geminin ubiquitination and triggers replication catastrophe upon ATR inhibition.
SPOP mutation induces replication over-firing by impairing Geminin ubiquitination and triggers replication catastrophe upon ATR inhibition.
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DOI：
10.1038/s41467-021-26049-6
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发表时间：
2021-10-01
影响因子：
16.6
通讯作者：
Huang H
中科院分区：
文献类型：
--
作者：
Ma J;Shi Q;Cui G;Sheng H;Botuyan MV;Zhou Y;Yan Y;He Y;Wang L;Wang Y;Mer G;Ye D;Wang C;Huang H
Geminin及其结合伴侣Cdt 1对DNA复制的调节至关重要。在这里，我们表明，CULLIN 3 E3泛素连接酶接头蛋白SPOP结合在内源性水平的Geminin和调节DNA复制。SPOP促进K27连接的非降解性多聚泛素化的Geminin在赖氨酸残基100和127。Geminin的这种多泛素化通过间接阻断Cdt 1与MCM蛋白复合物的结合（DNA解旋和复制所需的相互作用）来防止DNA复制过度。SPOP在某些人类癌症类型中经常发生突变，并与肿瘤发生有关。我们发现，与癌症相关的SPOP突变损害了Geminin K27连接的多聚泛素化，并诱导复制起点过度放电和重新复制。SPOP突变引起的复制应激在ATR抑制后引发复制灾难和细胞死亡。我们的研究结果揭示了SPOP在防止DNA复制过度和基因组不稳定性方面的肿瘤抑制作用，并表明SPOP突变的肿瘤可能对ATR抑制剂治疗敏感。Geminin-Cdt 1在DNA复制调控中起重要作用。在这里，作者揭示了CULLIN 3 E3泛素连接酶接头蛋白SPOP通过影响Geminin泛素化来防止DNA复制过激活和基因组不稳定性。
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.
影响因子：
3.5
作者：
Suchyta M;Miotto B;McGarry TJ
通讯作者：
McGarry TJ
DOI：
10.1242/dev.068676
发表时间：
2012-01
期刊：
Development (Cambridge, England)
影响因子：
--
作者：
Kisielewska J;Blow JJ
通讯作者：
Blow JJ