Phosphorylation-mediated disassembly of C-terminal binding protein 2 tetramer impedes epigenetic silencing of pluripotency in mouse embryonic stem cells
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.
Authors
- Hanbyeol Kim (ORCID: https://orcid.org/0000-0003-3387-2799)
- Ye‐Eun Jung (ORCID: https://orcid.org/0000-0002-5329-7958)
- Sojung Kwak
- Chul‐Hwan Lee (ORCID: https://orcid.org/0000-0003-0643-0100)
- Eun‐Jung Cho (ORCID: https://orcid.org/0000-0002-6610-5329)
- Han‐Teo Lee (ORCID: https://orcid.org/0000-0003-1840-6749)
- Hong‐Duk Youn (ORCID: https://orcid.org/0000-0001-9741-8566)
- Sun‐Shin Cha (ORCID: https://orcid.org/0000-0002-0913-8706)
- Sangho Lee (ORCID: https://orcid.org/0000-0003-4011-2317)
- Tae Wan Kim (ORCID: https://orcid.org/0000-0002-0831-6881)
- Jaehyeon Kim (ORCID: https://orcid.org/0000-0002-0712-1628)
- Jinmi Choi (ORCID: https://orcid.org/0000-0002-4909-9473)
- Young Ah Kim (ORCID: https://orcid.org/0000-0002-1769-3208)
Institutions
- Ewha Womans University (KR)
- Seoul National University (KR)
- Daegu Gyeongbuk Institute of Science and Technology (KR)
- New Generation University College (ET)
- Seoul National University Hospital (KR)
- Korea Pharma (South Korea) (KR)
- National University College (PR)
- Korea Research Institute of Bioscience and Biotechnology (KR)
- Sungkyunkwan University (KR)
Publication Details
- Journal
- Nucleic Acids Research
- Published
- 2024-11-26
- DOI
- https://doi.org/10.1093/nar/gkae1076
- Citations
- 3
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 0.70
Funders
- National Research Foundation
- Seoul National University
- National Research Foundation of Korea
- Seoul National University Hospital