The multifunctional protein PACS-1 is required for HDAC2- and HDAC3-dependent chromatin maturation and genomic stability

Chinnadurai Mani, Kaushlendra Tripathi, Shan Luan, David W. Clark, Joel F. Andrews, Alessandro Vindigni, Gary Thomas, Komaraiah Palle

Research output: Contribution to journalArticle

Abstract

Phosphofurin acidic cluster sorting protein-1 (PACS-1) is a multifunctional membrane traffic regulator that plays important roles in organ homeostasis and disease. In this study, we elucidate a novel nuclear function for PACS-1 in maintaining chromosomal integrity. PACS-1 progressively accumulates in the nucleus during cell cycle progression, where it interacts with class I histone deacetylases 2 and 3 (HDAC2 and HDAC3) to regulate chromatin dynamics by maintaining the acetylation status of histones. PACS-1 knockdown results in the proteasome-mediated degradation of HDAC2 and HDAC3, compromised chromatin maturation, as indicated by elevated levels of histones H3K9 and H4K16 acetylation, and, consequently, increased replication stress-induced DNA damage and genomic instability.

Original languageEnglish
Pages (from-to)2583-2596
Number of pages14
JournalOncogene
Volume39
Issue number12
DOIs
StatePublished - Mar 19 2020
Externally publishedYes

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