The essential G₁-cyclin, CCND1, is frequently overexpressed in cancer, contributing to tumorigenesis by driving cell-cycle progression. D-type cyclins are rate-limiting regulators of G₁-S progression in mammalian cells via their ability to bind and activate CDK4 and CDK6. In addition, cyclin D1 conveys kinase-independent transcriptional functions of cyclin D1. Here we report that cyclin D1 associates with H2B^S14 via an intrinsically disordered domain (IDD). The same region of cyclin D1 was necessary for the induction of aneuploidy, induction of the DNA damage response, cyclin D1-mediated recruitment into chromatin, and CIN gene transcription. In response to DNA damage H2B^S14 phosphorylation occurs, resulting in co-localization with γH2AX in DNA damage foci. Cyclin D1 ChIP seq and γH2AX ChIP seq revealed ~14% overlap. As the cyclin D1 IDD functioned independently of the CDK activity to drive CIN, the IDD domain may provide a rationale new target to complement CDK-extinction strategies.

必需的 G ₁ -细胞周期蛋白CCND1在癌症中经常过度表达，通过驱动细胞周期进展促进肿瘤发生。D 型细胞周期蛋白通过其结合和激活 CDK4 和 CDK6 的能力，成为哺乳动物细胞中G ₁ -S 进程的限速调节剂。此外，细胞周期蛋白 D1 还具有激酶独立的转录功能。在此，我们报告细胞周期蛋白 D1通过本质无序结构域 (IDD)与 H2B ^S14结合。细胞周期蛋白 D1 的同一区域对于诱导非整倍性、诱导 DNA 损伤反应、细胞周期蛋白 D1 介导的染色质招募和 CIN 基因转录是必需的。为了响应 DNA 损伤，H2B ^S14发生磷酸化，导致与 DNA 损伤灶中的 γH2AX 共定位。Cyclin D1 ChIP seq 和 γH2AX ChIP seq 显示约 14% 的重叠。由于细胞周期蛋白 D1 IDD 的功能独立于 CDK 活性来驱动 CIN，因此 IDD 结构域可能提供一个合理的新靶点来补充 CDK 灭绝策略。