On May 30, 2025, a research team led by Prof. Kang Tiebang and Prof. Wu Yuanzhong at Sun Yat-sen University Cancer Center published a study in Science titled "ASB7 is a Negative Regulator of H3K9me3 Homeostasis." The research reveals that ASB7 amplification causes genomic instability and confers tumor sensitivity to PARP inhibitors (PARPi), potentially offering new therapeutic strategies for patients with ASB7-amplified tumors.

Histone H3 lysine 9 trimethylation (H3K9me3) plays critical roles in maintaining heterochromatin structure, gene silencing, and DNA damage repair. Dysregulation of H3K9me3 can lead to genomic instability and cancer development. The establishment of H3K9me3 depends on the reader protein HP1 recognizing pre-existing modifications and recruiting the writer methyltransferase SUV39H1, which methylates adjacent newly incorporated histones to form a "read-write" positive feedback loop. This process requires strict regulation to prevent excessive H3K9me3 deposition and aberrant heterochromatin formation. However, mechanisms restricting this positive feedback to maintain H3K9me3 homeostasis in higher organisms remain unclear.

Through an unbiased genome-scale CRISPR-Cas9 screen, the team identified the ASB7 E3 ubiquitin ligase complex as a core negative regulator of H3K9me3. Mechanistically, HP1 recruits ASB7 to heterochromatin to promote SUV39H1 degradation. This process is tightly regulated by the cell cycle kinase CDK1-Cyclin B1. During mitosis, CDK1 phosphorylates ASB7, preventing its interaction with SUV39H1, thereby stabilizing SUV39H1 and enabling H3K9me3 restoration in subsequent cell cycles. This study reveals a dynamic regulatory circuit involving HP1, SUV39H1, and ASB7 governing H3K9me3 homeostasis in mammalian somatic cells (including tumor cells), ensuring faithful epigenetic inheritance while preventing excessive heterochromatin formation.

H3K9me3 modification occurs at DNA double-strand break (DSB) sites to activate repair pathways. ASB7 amplification in multiple tumor types reduces H3K9me3 levels at DSB sites, impairing homologous recombination repair (HRR). Cellular and animal experiments demonstrate that high ASB7 expression enhances tumor sensitivity to PARP inhibitors. These findings suggest patients with ASB7-amplified tumors may represent a potential beneficiary population for PARP inhibitor therapy.

Zhou Liwen, Associate Professor from the Experimental Research Department of Sun Yat-sen University Cancer Center, Chen Zhenxuan, a Master's candidate, and Zou Yezi, a Ph.D. candidate from Sun Yat-sen University School of Medicine, are the co-first authors of the paper. Prof. Kang Tiebang and Associate Prof. Wu Yuanzhong, from the Experimental Research Department of Sun Yat-sen University Cancer Center, are the corresponding authors.

Written by: Prof. Wu Yuanzhong, Experimental Research Department

Original Link: https://www.science.org/doi/10.1126/science.adq7408