Lee Han-Teo, Kim Young Ah, Lee Sangho, Jung Ye-Eun, Kim Hanbyeol, Kim Tae Wan, Kwak Sojung, Kim Jaehyeon, Lee Chul-Hwan, Cha Sun-Shin, Choi Jinmi, Cho Eun-Jung, Youn Hong-Duk
Stochastic Stemness Research Center, Department of Biomedical Science, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.
Ischemic/Hypoxic Disease Institute, Seoul National University Medical Research Center, Seoul 03080, Republic of Korea.
Nucleic Acids Res. 2024 Dec 11;52(22):13706-13722. doi: 10.1093/nar/gkae1076.
Cells need to overcome both intrinsic and extrinsic threats. Although pluripotency is associated with damage responses, how stem cells respond to DNA damage remains controversial. Here, we elucidate that DNA damage activates Chk2, leading to the phosphorylation of serine 164 on C-terminal binding protein 2 (Ctbp2). The phosphorylation of Ctbp2 induces the disruption of Ctbp2 tetramer, weakening interactions with zinc finger proteins, leading to the dissociation of phosphorylated Ctbp2 from chromatin. This transition to a monomeric state results in the separation of histone deacetylase 1 from Ctbp2, consequently slowing the rate of H3K27 deacetylation. In contrast to the nucleosome remodeling and deacetylase complex, phosphorylated Ctbp2 increased binding affinity to polycomb repressive complex (PRC)2, interacting through the N-terminal domain of Suz12. Through this domain, Ctbp2 competes with Jarid2, inhibiting the function of PRC2. Thus, the phosphorylation of Ctbp2 under stress conditions represents a precise mechanism aimed at preserving stemness traits by inhibiting permanent transcriptional shutdown.
细胞需要克服内在和外在的威胁。尽管多能性与损伤反应相关，但干细胞如何应对DNA损伤仍存在争议。在此，我们阐明DNA损伤会激活Chk2，导致C端结合蛋白2（Ctbp2）的丝氨酸164磷酸化。Ctbp2的磷酸化诱导Ctbp2四聚体的破坏，削弱与锌指蛋白的相互作用，导致磷酸化的Ctbp2从染色质上解离。这种向单体状态的转变导致组蛋白去乙酰化酶1与Ctbp2分离，从而减缓H3K27去乙酰化的速率。与核小体重塑和去乙酰化酶复合物相反，磷酸化的Ctbp2增加了与多梳抑制复合物（PRC）2的结合亲和力，通过Suz12的N端结构域相互作用。通过该结构域，Ctbp2与Jarid2竞争，抑制PRC2的功能。因此，应激条件下Ctbp2的磷酸化代表了一种精确的机制，可以通过抑制永久性转录关闭来维持干细胞特性。
