Prives Carol, Gottifredi Vanesa
Department of Biological Sciences, Columbia University, New York, New York, USA.
Cell Cycle. 2008 Dec 15;7(24):3840-6. doi: 10.4161/cc.7.24.7243. Epub 2008 Dec 21.
The contribution of error-prone DNA polymerases to the DNA damage response has been a subject of great interest in the last decade. Error-prone polymerases are required for translesion DNA synthesis (TLS), a process that involves synthesis past a DNA lesion. Under certain circumstances, TLS polymerases can achieve bypass with good efficiency and fidelity. However, they can also in some cases be mutagenic, and so negative regulators of TLS polymerases would have the important function of inhibiting their recruitment to undamaged DNA templates. Recent work from Livneh's and our groups have provided evidence regarding the role of the cyclin kinase inhibitor p21 as a negative regulator of TLS. Interestingly, both the cyclin dependent kinase (CDK) and proliferating cell nuclear antigen (PCNA) binding domains of p21 are involved in different aspects of the modulation of TLS, affecting both the interaction between PCNA and the TLS-specific pol eta as well as PCNA ubiquitination status. In line with this, p21 was shown to reduce the efficiency but increase the accuracy of TLS. Hence, in absence of DNA damage p21 may work to impede accidental loading of pol eta to undamaged DNA and avoid consequential mutagenesis. After UV irradiation, when TLS plays a decisive role, p21 is progressively degraded. This might allow gradual release of replication fork blockage by TLS polymerases. For these reasons, in higher eukaryotes p21 might represent a key regulator of the equilibrium between mutagenesis and cell survival.
易错DNA聚合酶在DNA损伤应答中的作用在过去十年中一直是备受关注的课题。跨损伤DNA合成（TLS）需要易错聚合酶，这一过程涉及越过DNA损伤进行合成。在某些情况下，TLS聚合酶能够高效且准确地实现跨越损伤的合成。然而，在某些情况下它们也可能具有致突变性，因此TLS聚合酶的负调控因子具有抑制其募集到未损伤DNA模板的重要功能。Livneh团队和我们团队最近的研究提供了关于细胞周期蛋白激酶抑制剂p21作为TLS负调控因子作用的证据。有趣的是，p21的细胞周期蛋白依赖性激酶（CDK）结合域和增殖细胞核抗原（PCNA）结合域都参与了TLS调控的不同方面，影响PCNA与TLS特异性聚合酶η之间的相互作用以及PCNA的泛素化状态。与此一致，p21被证明会降低TLS的效率但提高其准确性。因此，在没有DNA损伤的情况下，p21可能会阻止聚合酶η意外加载到未损伤的DNA上，避免由此产生的诱变。紫外线照射后，当TLS起决定性作用时，p21会逐渐降解。这可能会使TLS聚合酶逐渐解除对复制叉的阻滞。基于这些原因，在高等真核生物中，p21可能是诱变与细胞存活之间平衡的关键调节因子。
