The CRL4DTL E3 ligase induces degradation of the DNA replication initiation factor TICRR/TRESLIN specifically during S phase.
The CRL4DTL E3 ligase induces degradation of the DNA replication initiation factor TICRR/TRESLIN specifically during S phase.
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DOI：
10.1093/nar/gkab805
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发表时间：
2021-10-11
影响因子：
14.9
通讯作者：
Sansam CL
中科院分区：
文献类型：
--
作者：
Wittig KA;Sansam CG;Noble TD;Goins D;Sansam CL
在S期开始之前的G1期，建立了DNA复制程序，以确保基因组的准确和完整复制。在G1期，复制起点被许可，并且在S期进入时，这些复制起点的子集将形成活性复制体。严格调节活性复制体的数量对于防止复制应激诱导的DNA损伤至关重要。TICRR/TRESLIN对于DNA复制起始是必需的，并且TICRR的水平及其磷酸化决定了在S期期间起始的起点的数量。然而，调节TICRR蛋白水平的机制尚不清楚。因此，我们开始定义TICRR/TRESLIN蛋白在整个细胞周期中的动力学。在这里，我们发现TICRR水平在G1期很高，当细胞进入S期并开始DNA复制时，TICRR水平急剧下降。我们发现TICRR的降解特异性地发生在S期，并且依赖于泛素连接酶和蛋白酶体降解。使用两个靶向siRNA筛选，我们确定CRL 4DTL作为TICRR降解所需的cullin复合物。我们认为这种机制调节了可用于复制起始的TICRR蛋白的水平，确保了细胞在S期进展时有适当数量的活性起点。两个必需的限制性DNA复制因子在G1/S转换时通过CRL 4DTL E3泛素连接酶破坏TICRR/TRESLIN进行调节。
A DNA replication program, which ensures that the genome is accurately and wholly replicated, is established during G1, before the onset of S phase. In G1, replication origins are licensed, and upon S phase entry, a subset of these will form active replisomes. Tight regulation of the number of active replisomes is crucial to prevent replication stress-induced DNA damage. TICRR/TRESLIN is essential for DNA replication initiation, and the level of TICRR and its phosphorylation determine the number of origins that initiate during S phase. However, the mechanisms regulating TICRR protein levels are unknown. Therefore, we set out to define the TICRR/TRESLIN protein dynamics throughout the cell cycle. Here, we show that TICRR levels are high during G1 and dramatically decrease as cells enter S phase and begin DNA replication. We show that degradation of TICRR occurs specifically during S phase and depends on ubiquitin ligases and proteasomal degradation. Using two targeted siRNA screens, we identify CRL4DTL as a cullin complex necessary for TICRR degradation. We propose that this mechanism moderates the level of TICRR protein available for replication initiation, ensuring the proper number of active origins as cells progress through S phase. Two essential, limiting DNA replication factors are regulated at the G1/S transition through the destruction of TICRR/TRESLIN by the CRL4DTL E3 ubiquitin ligase.
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影响因子：
64.8
作者：
Bartkova, Jirina;Rezaei, Nousin;Gorgoulis, Vassilis G.
通讯作者：
Gorgoulis, Vassilis G.
影响因子：
64.8
作者：
Di Micco, Raffaella;Fumagalli, Marzia;di Fagagna, Fabrizio d'Adda
通讯作者：
di Fagagna, Fabrizio d'Adda
影响因子：
16
作者：
Buisson R;Boisvert JL;Benes CH;Zou L
通讯作者：
Zou L
影响因子：
14.8
作者：
Forment JV;Jackson SP
通讯作者：
Jackson SP
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影响因子：
3.5
作者：
Hannah J;Zhou P
通讯作者：
Zhou P