Although mismatch repair (MMR) is essential for correcting DNA replication errors, it can also recognize other lesions, such as oxidized bases. In G0 and G1, MMR is kept in check through unknown mechanisms as it is error-prone during these cell cycle phases. We show that in mammalian cells, D-type cyclins are recruited to sites of oxidative DNA damage in a PCNA- and p21-dependent manner. D-type cyclins inhibit the proteasomal degradation of p21, which competes with MMR proteins for binding to PCNA, thereby inhibiting MMR. The ability of D-type cyclins to limit MMR is CDK4- and CDK6-independent and is conserved in G0 and G1. At the G1/S transition, the timely, cullin-RING ubiquitin ligase (CRL)-dependent degradation of D-type cyclins and p21 enables MMR activity to efficiently repair DNA replication errors. Persistent expression of D-type cyclins during S-phase inhibits the binding of MMR proteins to PCNA, increases the mutational burden, and promotes microsatellite instability.

中文翻译：

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D型细胞周期蛋白在调节DNA错配修复中的CDK独立作用

尽管错配修复 (MMR) 对于纠正 DNA 复制错误至关重要，但它也可以识别其他损伤，例如氧化碱基。在 G0 和 G1 阶段，MMR 通过未知机制受到控制，因为它在这些细胞周期阶段容易出错。我们发现，在哺乳动物细胞中，D 型细胞周期蛋白以 PCNA 和 p21 依赖性方式被募集到 DNA 氧化损伤位点。 D 型细胞周期蛋白抑制 p21 的蛋白酶体降解，p21 与 MMR 蛋白竞争结合 PCNA，从而抑制 MMR。 D 型细胞周期蛋白限制 MMR 的能力不依赖于 CDK4 和 CDK6，并且在 G0 和 G1 中保守。在 G1/S 转变时，Cullin-RING 泛素连接酶 (CRL) 依赖性的 D 型细胞周期蛋白和 p21 及时降解使 MMR 活性能够有效修复 DNA 复制错误。 S 期 D 型细胞周期蛋白的持续表达会抑制 MMR 蛋白与 PCNA 的结合，增加突变负担，并促进微卫星不稳定。