Prostate cancer-associated SPOP mutations lead to genomic instability through disruption of the SPOP-HIPK2 axis.
Prostate cancer-associated SPOP mutations lead to genomic instability through disruption of the SPOP-HIPK2 axis.
复制标题
前列腺癌相关的 SPOP 突变通过破坏 SPOP HIPK2 轴导致基因组不稳定
DOI：
10.1093/nar/gkab489
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发表时间：
2021-07-09
影响因子：
14.9
通讯作者：
Gao K
中科院分区：
文献类型：
--
作者：
Jin X;Qing S;Li Q;Zhuang H;Shen L;Li J;Qi H;Lin T;Lin Z;Wang J;Cao X;Yang J;Ma Q;Cong L;Xi Y;Fang S;Meng X;Gong Z;Ye M;Wang S;Wang C;Gao K
斑点型Poz蛋白（SPOP）是一种E3泛素连接酶接头，是前列腺癌中最常见的突变基因。前列腺癌的SPOP突变亚型显示出高度的基因组不稳定性，但导致这种表型的潜在机制在很大程度上仍然未知。在这里，我们报告说，在DNA损伤，SPOP是由ATM丝氨酸/苏氨酸激酶，这增强了SPOP的同源结构域相互作用蛋白激酶2（HIPK 2）的结合，在非降解泛素化的HIPK 2的Ser 119磷酸化。这种修饰随后增加HIPK 2对HP 1 γ的磷酸化活性，然后促进HP 1 γ从三甲基化（Lys 9）组蛋白H3（H3 K9 me 3）解离以启动DNA损伤修复。此外，SPOP对HIPK 2-HP 1 γ轴的作用被前列腺癌相关的SPOP突变消除。我们的研究结果为SPOP突变驱动的前列腺癌基因组不稳定性的分子机制提供了新的见解。
Speckle-type Poz protein (SPOP), an E3 ubiquitin ligase adaptor, is the most frequently mutated gene in prostate cancer. The SPOP-mutated subtype of prostate cancer shows high genomic instability, but the underlying mechanisms causing this phenotype are still largely unknown. Here, we report that upon DNA damage, SPOP is phosphorylated at Ser119 by the ATM serine/threonine kinase, which potentiates the binding of SPOP to homeodomain-interacting protein kinase 2 (HIPK2), resulting in a nondegradative ubiquitination of HIPK2. This modification subsequently increases the phosphorylation activity of HIPK2 toward HP1γ, and then promotes the dissociation of HP1γ from trimethylated (Lys9) histone H3 (H3K9me3) to initiate DNA damage repair. Moreover, the effect of SPOP on the HIPK2-HP1γ axis is abrogated by prostate cancer-associated SPOP mutations. Our findings provide new insights into the molecular mechanism of SPOP mutations-driven genomic instability in prostate cancer.
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影响因子：
7
作者：
Imberg-Kazdan K;Ha S;Greenfield A;Poultney CS;Bonneau R;Logan SK;Garabedian MJ
通讯作者：
Garabedian MJ
影响因子：
14.9
作者：
Hjorth-Jensen K;Maya-Mendoza A;Dalgaard N;Sigurðsson JO;Bartek J;Iglesias-Gato D;Olsen JV;Flores-Morales A
通讯作者：
Flores-Morales A
SPOP 通过调节 CYCLIN E1 稳定性来抑制前列腺癌。
影响因子：
12.4
作者：
Ju LG;Zhu Y;Long QY;Li XJ;Lin X;Tang SB;Yin L;Xiao Y;Wang XH;Li L;Zhang L;Wu M
通讯作者：
Wu M
DOI：
10.1016/j.mrgentox.2008.04.005
发表时间：
2008-06-30
影响因子：
1.9
作者：
Guillamet, Emma;Creus, Amadeu;Marcos, Ricardo
通讯作者：
Marcos, Ricardo
影响因子：
82.9
作者：
Dai X;Gan W;Li X;Wang S;Zhang W;Huang L;Liu S;Zhong Q;Guo J;Zhang J;Chen T;Shimizu K;Beca F;Blattner M;Vasudevan D;Buckley DL;Qi J;Buser L;Liu P;Inuzuka H;Beck AH;Wang L;Wild PJ;Garraway LA;Rubin MA;Barbieri CE;Wong KK;Muthuswamy SK;Huang J;Chen Y;Bradner JE;Wei W
通讯作者：
Wei W