p21Waf/CIP1 is a small unstructured protein that binds and inactivates cyclin-dependent kinases (CDKs). To this end, p21 levels increase following the activation of the p53 tumor suppressor. CDK inhibition by p21 triggers cell-cycle arrest in the G1 and G2 phases of the cell cycle. In the absence of exogenous insults causing replication stress, only residual p21 levels are prevalent that are insufficient to inhibit CDKs. However, research from different laboratories has demonstrated that these residual p21 levels in the S phase control DNA replication speed and origin firing to preserve genomic stability. Such an S-phase function of p21 depends fully on its ability to displace partners from chromatin-bound proliferating cell nuclear antigen (PCNA). Vice versa, PCNA also regulates p21 by preventing its upregulation in the S phase, even in the context of robust p21 induction by γ irradiation. Such a tight regulation of p21 in the S phase unveils the potential that CDK-independent functions of p21 may have for the improvement of cancer treatments.

中文翻译：

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p21 在 DNA 复制中的 CDK 独立和 PCNA 依赖性功能

p21Waf/CIP1 是一种小的非结构化蛋白质，可结合并灭活细胞周期蛋白依赖性激酶 (CDK)。为此，p53 肿瘤抑制因子激活后 p21 水平增加。p21 对 CDK 的抑制会在细胞周期的 G1 和 G2 期触发细胞周期停滞。在没有引起复制压力的外源性损伤的情况下，只有残留的 p21 水平普遍存在，不足以抑制 CDK。然而，来自不同实验室的研究表明，S 期中的这些残留 p21 水平控制 DNA 复制速度和起点发射，以保持基因组稳定性。p21 的这种 S 期功能完全取决于它从染色质结合的增殖细胞核抗原 (PCNA) 中置换伴侣的能力。反之亦然，PCNA 还通过阻止其在 S 期的上调来调节 p21，即使在通过 γ 辐射强烈诱导 p21 的情况下。在 S 期对 p21 的这种严格调节揭示了 p21 的 CDK 独立功能可能具有改善癌症治疗的潜力。