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Nucleic Acids Res., Nov 26 2024, gkae1076 | https://doi.org/10.1093/nar/gkae1076
Phosphorylation-mediated disassembly of C-terminal binding protein 2 tetramer impedes epigenetic silencing of pluripotency in mouse embryonic stem cells
Han-Teo Lee1,2, Young Ah Kim1, Sangho Lee1, Ye-Eun Jung3, Hanbyeol Kim1,4, Tae Wan Kim5, Sojung Kwak6, Jaehyeon Kim1, Chul-Hwan Lee1,2,4, Sun-Shin Cha3,7, Jinmi Choi8, Eun-Jung Cho8 and Hong-Duk Youn1,2,*
1Stochastic Stemness Research Center, Department of Biomedical Science, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
2Ischemic/Hypoxic Disease Institute, Seoul National University Medical Research Center, Seoul 03080, Republic of Korea
3Department of Chemistry and Nanoscience, Ewha Womans University, Seoul 03760, Republic of Korea
4Department of Pharmacology, Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
5Department of Interdisciplinary Engineering, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Republic of Korea
6Developmental Biology Laboratory, Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea
7R&D Division, TODD PHARM CO. LTD., Seoul 03760, Republic of Korea
8School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
*To whom correspondence should be addressed. : Hong-Duk Youn
1Stochastic Stemness Research Center, Department of Biomedical Science, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
2Ischemic/Hypoxic Disease Institute, Seoul National University Medical Research Center, Seoul 03080, Republic of Korea
3Department of Chemistry and Nanoscience, Ewha Womans University, Seoul 03760, Republic of Korea
4Department of Pharmacology, Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
5Department of Interdisciplinary Engineering, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Republic of Korea
6Developmental Biology Laboratory, Environmental Disease Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea
7R&D Division, TODD PHARM CO. LTD., Seoul 03760, Republic of Korea
8School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea
*To whom correspondence should be addressed. : Hong-Duk Youn
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.
논문정보
- Research article
- 2024년 11월 (BRIC 등록일 2024-11-27)
- 국내 연구진
- 생명과학 > 유전자발현
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