ASB7 is a negative regulator of H3K9me3 homeostasis
The maintenance of histone H3 lysine 9 trimethylation (H3K9me3) involves the recognition of preexisting modifications by heterochromatin protein 1 (HP1), which recruits the methyltransferase suppressor of variegation 3-9 homolog 1 (SUV39H1) to methylate the adjacent newly incorporated histones, establishing a positive feedback loop. However, how this positive feedback is restricted to maintain H3K9me3 homeostasis remains largely unknown. We performed an unbiased genome-scale CRISPR-Cas9 screen and identified CUL5<sup>ASB7</sup> E3 ubiquitin ligase as a negative regulator of H3K9me3. ASB7 is recruited to heterochromatin by HP1 and promotes SUV39H1 degradation. During mitosis, cyclin-dependent kinase 1 (CDK1) phosphorylates ASB7, preventing its interaction with SUV39H1, leading to SUV39H1 stabilization and H3K9me3 restoration. Our findings reveal a dynamic circuit involving HP1, SUV39H1, and ASB7 that governs H3K9me3 homeostasis, ensuring faithful epigenetic inheritance and preventing excessive heterochromatin formation.
Authors
- Jiahui Lin
- Song Gao (ORCID: https://orcid.org/0000-0001-7427-6681)
- Hongwen Zhu (ORCID: https://orcid.org/0000-0002-2116-4245)
- Yuanzhong Wu (ORCID: https://orcid.org/0000-0002-3577-7069)
- Ziwen Wang (ORCID: https://orcid.org/0000-0002-1678-7624)
- Minglu Zhu (ORCID: https://orcid.org/0000-0001-6652-2133)
- Yuxin Yin (ORCID: https://orcid.org/0000-0003-4102-0043)
- Ruhua Zhang (ORCID: https://orcid.org/0000-0003-3665-7189)
- Tiebang Kang (ORCID: https://orcid.org/0000-0001-8805-4174)
- Hu Zhou (ORCID: https://orcid.org/0000-0001-7006-4737)
- Miner Xie (ORCID: https://orcid.org/0009-0003-2790-4616)
- Jiali Chen (ORCID: https://orcid.org/0000-0002-3101-104X)
- Xia Zhang (ORCID: https://orcid.org/0009-0005-1159-9631)
- Ziyao Huang
- Zifeng Wang (ORCID: https://orcid.org/0000-0001-7400-5224)
- Zhilong Chen (ORCID: https://orcid.org/0000-0003-4759-3598)
- Yezi Zou
- Meifang Zhang (ORCID: https://orcid.org/0000-0002-9981-7189)
- Liwen Zhou (ORCID: https://orcid.org/0000-0003-1092-3768)
- Lisi Zheng
Institutions
- Sun Yat-sen University (CN)
- Peking University (CN)
- Shanghai Institute of Materia Medica (CN)
- Guangzhou First People's Hospital (CN)
- Sun Yat-sen University Cancer Center (CN)
- State Key Laboratory of Oncology in South China
- South China University of Technology (CN)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Science
- Published
- 2025-05-29
- DOI
- https://doi.org/10.1126/science.adq7408
- Citations
- 11
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 10.30