Characterization of human Spartan/C1orf124, an ubiquitin-PCNA interacting regulator of DNA damage tolerance.
Characterization of human Spartan/C1orf124, an ubiquitin-PCNA interacting regulator of DNA damage tolerance.
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DOI：
10.1093/nar/gks850
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发表时间：
2012-11
影响因子：
14.9
通讯作者：
Haracska L
中科院分区：
文献类型：
--
作者：
Juhasz S;Balogh D;Hajdu I;Burkovics P;Villamil MA;Zhuang Z;Haracska L
未修复的 DNA 损伤可能会阻止正在进行的复制叉，从而可能导致叉崩溃、突变增加和基因组不稳定。 DNA 损伤的复制依赖于增殖细胞核抗原 (PCNA) 的单泛素化和多泛素化，这分别能够实现跨损伤合成 (TLS) 和模板切换。 PCNA 的动态泛素化和去泛素化确保了正确的复制叉救援；然而，迄今为止，人们对其监管知之甚少。在这里，我们发现人类 Spartan/C1orf124 蛋白提供了更高的细胞水平的泛素化 PCNA，通过它调节 DNA 损伤耐受途径的选择。我们发现 Spartan 被招募到复制应激位点，这一过程依赖于其 PCNA 和泛素相互作用结构域以及 RAD18 PCNA 泛素连接酶。 Spartan 与泛素修饰的 PCNA 优先结合，可防止 PCNA 被泛素特异性蛋白酶 1 去泛素化，并促进 TLS 聚合酶进入复制叉。同时，Spartan 的消耗会导致对 DNA 损伤剂的敏感性增加，并导致姐妹染色单体交换水平升高。我们提出，Spartan 通过调节对停滞复制叉的拯救选择来促进基因组稳定性，其机制包括与泛素缀合的 PCNA 相互作用以及防止 PCNA 去泛素化。
Unrepaired DNA damage may arrest ongoing replication forks, potentially resulting in fork collapse, increased mutagenesis and genomic instability. Replication through DNA lesions depends on mono- and polyubiquitylation of proliferating cell nuclear antigen (PCNA), which enable translesion synthesis (TLS) and template switching, respectively. A proper replication fork rescue is ensured by the dynamic ubiquitylation and deubiquitylation of PCNA; however, as yet, little is known about its regulation. Here, we show that human Spartan/C1orf124 protein provides a higher cellular level of ubiquitylated-PCNA by which it regulates the choice of DNA damage tolerance pathways. We find that Spartan is recruited to sites of replication stress, a process that depends on its PCNA- and ubiquitin-interacting domains and the RAD18 PCNA ubiquitin ligase. Preferential association of Spartan with ubiquitin-modified PCNA protects against PCNA deubiquitylation by ubiquitin-specific protease 1 and facilitates the access of a TLS polymerase to the replication fork. In concert, depletion of Spartan leads to increased sensitivity to DNA damaging agents and causes elevated levels of sister chromatid exchanges. We propose that Spartan promotes genomic stability by regulating the choice of rescue of stalled replication fork, whose mechanism includes its interaction with ubiquitin-conjugated PCNA and protection against PCNA deubiquitylation.
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影响因子：
64.8
作者：
通讯作者：
--
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：
3.5
作者：
Fox JT;Lee KY;Myung K
通讯作者：
Myung K
影响因子：
4.8
作者：
Cohn, Martin A.;Kee, Younghoon;D'Andrea, Alan D.
通讯作者：
D'Andrea, Alan D.
DOI：
10.1073/pnas.0805685105
发表时间：
2008-08-26
影响因子：
11.1
作者：
Motegi, Akira;Liaw, Hung-Jiun;Myung, Kyungjae
通讯作者：
Myung, Kyungjae