The modulation of PCNA ubiquitination by p21 and its significance for DNA repair

而体外实验着重证明了p21对增殖细胞核抗原依赖的DNA的抑制作用。 复制和修复在细胞中进行的实验中很难得出类似的结论。 这可能至少部分取决于在S阶段阻止p21上调的汇聚信号。我们 已经发现了一项有趣的观察，即一些基因毒性治疗会导致短暂性或 S期永久停滞协同促进p21下调和增殖细胞核抗原泛素化。此外， 稳定的p21表达负向调节增殖细胞核抗原泛素化，这是一种转录后修饰 滑动夹与其DNA修复相关活动有关。这一观察促使我们开始研究小说 P21对增殖细胞核抗原的调控。 我们建议探讨紫外线照射后p21依赖抑制增殖细胞核抗原亚突变的机制。 辐射。这也将有助于识别其他调节增殖细胞核抗原泛素化的分子。 是p21的靶标。P21降解和增殖细胞核抗原泛素化之间的联系也将使 确定协调这些事件的上游路径。稳定的p21基因对细胞存活的影响 在上述基因毒性处理过程中的表达可能揭示了p21的生物学相关性。 下调并可能对癌症治疗有重要意义。

While in vitro experiments emphatically demonstrated the inhibitory effect of p21 on PCNA dependent DNA replication and repair it was much harder to arrive to similar conclusions in experiments performed in cells. This might depend, at least in part, on the convergent signals that prevent p21 up-regulation in S phase. We have come across the intriguing observation that a number of genotoxic treatments that induce transient or permanent arrest in S phase coordinately promote p21 down-regulation and PCNA ubiquitination. Moreover, stable p21 expression negatively modulates PCNA ubiquitination, a post-transcriptional modification of the sliding clamp relevant for its DNA repair-related activities. This observation prompt us to the study of novels aspects of PCNA regulation by p21. We propose to explore the mechanisms for p21 dependent inhibition of PCNA ubqiutination after UV irradiation. This will also facilitate the identification of other molecules that modulate PCNA ubiquitination and are targets of p21. The link between p21 degradation and PCNA ubiquitination will also allow the identification of pathways upstream that coordinate these events. The effects on cell survival of a stable p21 expression during the above mentioned genotoxic treatments might reveal the biological relevance of p21 down-regulation and might be significant for cancer therapy.