Phosphorylation-mediated disassembly of C-terminal binding protein 2 tetramer impedes epigenetic silencing of pluripotency in mouse embryonic stem cells.

IF 16.6 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Nucleic Acids Research Pub Date : 2024-12-11 DOI:10.1093/nar/gkae1076
Han-Teo Lee, Young Ah Kim, Sangho Lee, Ye-Eun Jung, Hanbyeol Kim, Tae Wan Kim, Sojung Kwak, Jaehyeon Kim, Chul-Hwan Lee, Sun-Shin Cha, Jinmi Choi, Eun-Jung Cho, Hong-Duk Youn
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Abstract

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.

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磷酸化介导的 C 端结合蛋白 2 四聚体解体阻碍了小鼠胚胎干细胞多能性的表观遗传沉默。
细胞需要克服内在和外在威胁。虽然全能性与损伤反应有关,但干细胞如何应对DNA损伤仍存在争议。在这里,我们阐明了DNA损伤激活Chk2,导致C端结合蛋白2(Ctbp2)上的丝氨酸164磷酸化。Ctbp2 的磷酸化会导致 Ctbp2 四聚体的破坏,削弱与锌指蛋白的相互作用,从而导致磷酸化的 Ctbp2 从染色质中解离。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,从而减缓了 H3K27 去乙酰化的速度。与核小体重塑和去乙酰化酶复合物相反,磷酸化的 Ctbp2 增加了与多角体抑制复合物(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,Ctbp2在胁迫条件下的磷酸化代表了一种精确的机制,旨在通过抑制永久性转录关闭来保持干性特征。
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来源期刊
Nucleic Acids Research
Nucleic Acids Research 生物-生化与分子生物学
CiteScore
27.10
自引率
4.70%
发文量
1057
审稿时长
2 months
期刊介绍: Nucleic Acids Research (NAR) is a scientific journal that publishes research on various aspects of nucleic acids and proteins involved in nucleic acid metabolism and interactions. It covers areas such as chemistry and synthetic biology, computational biology, gene regulation, chromatin and epigenetics, genome integrity, repair and replication, genomics, molecular biology, nucleic acid enzymes, RNA, and structural biology. The journal also includes a Survey and Summary section for brief reviews. Additionally, each year, the first issue is dedicated to biological databases, and an issue in July focuses on web-based software resources for the biological community. Nucleic Acids Research is indexed by several services including Abstracts on Hygiene and Communicable Diseases, Animal Breeding Abstracts, Agricultural Engineering Abstracts, Agbiotech News and Information, BIOSIS Previews, CAB Abstracts, and EMBASE.
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