PCNA-coupled p21 degradation after DNA damage: The exception that confirms the rule?
PCNA-coupled p21 degradation after DNA damage: The exception that confirms the rule?
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DOI：
10.1016/j.dnarep.2009.12.003
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发表时间：
2010-04-04
期刊：
影响因子：
3.8
通讯作者：
Gottifredi V
中科院分区：
文献类型：
--
作者：
Soria G;Gottifredi V
虽然许多DNA损伤治疗诱导p21积累的例子，p21上调作为遗传毒性应激的普遍反应的概念已经结束。令人信服的证据表明，当复制叉被阻断时，存在会聚信号负调节p21低于基础水平。此外，结论性报道将E3-连接酶CRL 4 CDT 2（CUL 4-DDB 1-CDT 2）鉴定为当诸如UV照射的处理触发复制叉应激时促进p21蛋白水解的酶复合物。p21与PCNA的相互作用是CRL 4 CDT 2驱动蛋白水解的先决条件。有趣的是，CRL 4 CDT 2依赖性蛋白水解不仅限于p21，还影响其他PCNA伴侣，包括专门的DNA聚合酶η（pol eta）。这些最近的发现是特别有趣的，因为已经显示UV诱导的p21降解是DNA损伤的有效pol η募集所必需的。在这里，我们回顾的结果，导致识别的分子机制，触发损伤诱导的PCNA偶联蛋白水解。我们提出了一个新的模型，其中CRL 4CDT 2依赖的蛋白质降解促进了顺序和动态交换PIP框轴承蛋白质之间的失速叉在translsion DNA合成（TLS）。此外，鉴于紧密的时空控制，CRL 4CDT 2驱动的蛋白水解能够赋予PCNA调节的过程，我们讨论了这种降解机制可能在其他分子开关与修复受损的DNA。
While many are the examples of DNA damaging treatments that induce p21 accumulation, the conception of p21 upregulation as the universal response to genotoxic stress has come to an end. Compelling evidences have demonstrated the existence of converging signals that negatively regulate p21 bellow basal levels when replication forks are blocked. Moreover, conclusive reports identified the E3-ligase CRL4CDT2 (CUL4-DDB1-CDT2) as the enzymatic complex that promotes p21 proteolysis when treatments such as UV irradiation trigger replication fork stress. A pre-requisite for CRL4CDT2-driven proteolysis is the interaction of p21 with PCNA. Interestingly as well, CRL4CDT2-dependent proteolysis is not limited to p21 and affects other PCNA partners, including the specialized DNA polymerase η(pol eta). These recent discoveries are particularly intriguing since the UV-induced degradation of p21 has been shown to be required for efficient pol η recruitment to DNA lesions. Herein we review the findings that lead to the identification of the molecular mechanism that triggers damage-induced PCNA-coupled protein proteolysis. We propose a novel model in which CRL4CDT2-dependent protein degradation facilitates a sequential and dynamic exchange between PIP box-bearing proteins at stall forks during Translesion DNA synthesis (TLS). Moreover, given the tight spatiotemporal control that CRL4CDT2-driven proteolysis is able to confer to PCNA-regulated processes, we discuss the impact that this degradation mechanism might have in other molecular switches associated with the repair of damaged DNA.
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影响因子：
3.8
作者：
Lehmann, Alan R.;Niimi, Atsuko;Green, Catherine M.
通讯作者：
Green, Catherine M.
DOI：
10.1073/pnas.021282898
发表时间：
2001-01-30
影响因子：
11.1
作者：
Gottifredi, V;Shieh, SY;Prives, C
通讯作者：
Prives, C
影响因子：
64.5
作者：
ELDEIRY, WS;TOKINO, T;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
影响因子：
5.3
作者：
Mattia, Melissa;Gottifredi, Vanesa;Prives, Carol
通讯作者：
Prives, Carol
影响因子：
10.5
作者：
Groisman, Regina;Kuraoka, Isao;Nakatani, Yoshihiro
通讯作者：
Nakatani, Yoshihiro