SPOP promotes transcriptional expression of DNA repair and replication factors to prevent replication stress and genomic instability.
SPOP promotes transcriptional expression of DNA repair and replication factors to prevent replication stress and genomic instability.
复制标题
DOI：
10.1093/nar/gky719
复制
发表时间：
2018-10-12
影响因子：
14.9
通讯作者：
Flores-Morales A
中科院分区：
文献类型：
--
作者：
Hjorth-Jensen K;Maya-Mendoza A;Dalgaard N;Sigurðsson JO;Bartek J;Iglesias-Gato D;Olsen JV;Flores-Morales A
SPOP是前列腺癌中最常见的点突变基因，它的突变与基因组高度不稳定和DNA同源重组修复缺陷有关，但这种缺陷背后的潜在机制目前尚不清楚。在这里，我们证明SPOP基因敲除会导致自发的复制压力和从复制分叉停滞中恢复的受损。我们发现，这与BRCA2、ATR、CHK1和RAD51等几个关键DNA修复和复制因子的表达减少有关。因此，SPOP基因敲除削弱了RAD51焦点的形成和CHK1对复制应激的激活，并损害了从复制分叉停滞中恢复的能力。SPOP相互作用组分析表明，野生型(WT)SPOP而不是突变型SPOP与多种蛋白质结合，参与转录、mRNA剪接和输出。与SPOP与转录、剪接和RNA输出复合体的关联一致，BRCA2、ATR、CHK1和RAD51的表达下降发生在转录水平。
Mutations in SPOP, the gene most frequently point-mutated in primary prostate cancer, are associated with a high degree of genomic instability and deficiency in homologous recombination repair of DNA but the underlying mechanisms behind this defect are currently unknown. Here we demonstrate that SPOP knockdown leads to spontaneous replication stress and impaired recovery from replication fork stalling. We show that this is associated with reduced expression of several key DNA repair and replication factors including BRCA2, ATR, CHK1 and RAD51. Consequently, SPOP knockdown impairs RAD51 foci formation and activation of CHK1 in response to replication stress and compromises recovery from replication fork stalling. An SPOP interactome analysis shows that wild type (WT) SPOP but not mutant SPOP associates with multiple proteins involved in transcription, mRNA splicing and export. Consistent with the association of SPOP with transcription, splicing and RNA export complexes, the decreased expression of BRCA2, ATR, CHK1 and RAD51 occurs at the level of transcription.
登录
查看更多内容
影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J
影响因子：
64.8
作者：
Burrell RA;McClelland SE;Endesfelder D;Groth P;Weller MC;Shaikh N;Domingo E;Kanu N;Dewhurst SM;Gronroos E;Chew SK;Rowan AJ;Schenk A;Sheffer M;Howell M;Kschischo M;Behrens A;Helleday T;Bartek J;Tomlinson IP;Swanton C
通讯作者：
Swanton C
DOI：
10.1083/jcb.200510130
发表时间：
2006-04-24
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bekker-Jensen S;Lukas C;Kitagawa R;Melander F;Kastan MB;Bartek J;Lukas J
通讯作者：
Lukas J
影响因子：
4
作者：
Daboussi, Fayza;Courbet, Sylvain;Lopez, Bernard S.
通讯作者：
Lopez, Bernard S.
影响因子：
16
作者：
Gan W;Dai X;Lunardi A;Li Z;Inuzuka H;Liu P;Varmeh S;Zhang J;Cheng L;Sun Y;Asara JM;Beck AH;Huang J;Pandolfi PP;Wei W
通讯作者：
Wei W