Istituto di Genetica Molecolare "Luigi Luca Cavalli-Sforza", Consiglio Nazionale delle Ricerche (CNR), Via Abbiategrasso 207, 27100 Pavia, Italy.
Dipartimento di Biologia e Biotecnologie, Università di Pavia, Via Ferrata 9, 27100 Pavia, Italy.
Int J Mol Sci. 2022 Jun 24;23(13):7058. doi: 10.3390/ijms23137058.
The p21 protein is an important player in the maintenance of genome stability through its function as a cyclin-dependent kinase inhibitor, leading to cell-cycle arrest after genotoxic damage. In the DNA damage response, p21 interacts with specific proteins to integrate cell-cycle arrest with processes such as transcription, apoptosis, DNA repair, and cell motility. By associating with Proliferating Cell Nuclear Antigen (PCNA), the master of DNA replication, p21 is able to inhibit DNA synthesis. However, to avoid conflicts with this process, p21 protein levels are finely regulated by pathways of proteasomal degradation during the S phase, and in all the phases of the cell cycle, after DNA damage. Several lines of evidence have indicated that p21 is required for the efficient repair of different types of genotoxic lesions and, more recently, that p21 regulates DNA replication fork speed. Therefore, whether p21 is an inhibitor, or rather a regulator, of DNA replication and repair needs to be re-evaluated in light of these findings. In this review, we will discuss the lines of evidence describing how p21 is involved in DNA repair and will focus on the influence of protein interactions and p21 stability on the efficiency of DNA repair mechanisms.
p21 蛋白作为细胞周期蛋白依赖性激酶抑制剂，在维持基因组稳定性方面发挥着重要作用，可导致细胞在遭受遗传毒性损伤后发生细胞周期停滞。在 DNA 损伤反应中，p21 与特定蛋白相互作用，将细胞周期停滞与转录、凋亡、DNA 修复和细胞迁移等过程整合在一起。通过与 DNA 复制的主调控因子增殖细胞核抗原（PCNA）结合，p21 能够抑制 DNA 合成。然而，为了避免与这一过程发生冲突，p21 蛋白水平在 S 期和细胞周期的所有阶段，通过蛋白酶体降解途径进行精细调节，以应对 DNA 损伤。有几条证据表明，p21 对于不同类型的遗传毒性损伤的有效修复是必需的，最近的研究表明，p21 还调节 DNA 复制叉速度。因此，需要根据这些发现重新评估 p21 对 DNA 复制和修复的抑制作用，或者说它对 DNA 复制和修复的调节作用。在这篇综述中，我们将讨论描述 p21 如何参与 DNA 修复的证据，并将重点放在蛋白相互作用和 p21 稳定性对 DNA 修复机制效率的影响上。
