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

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.

Integration and Comparison of Transcriptomic and Proteomic Data for Meningioma

“…Thus, we elected not to exclude discordant expression as these trends may also harbour therapeutic targets and reveal further insight into altered gene expression between low-and high-grade meningioma. Among those transcripts/proteins displaying the strongest discordant expression with high protein but low transcript LFC in grade III tumours were the Na + /HCO 3 co-transporter SLC4A4, previously shown to contribute to the proliferation, migration and invasion of a breast cancer cell line [58], and the phosphofurin acidic cluster sorting protein-1, PACS1, recently revealed to function in the nucleus as an epigenetic regulator to promote oncogenic replication and progression [58,59]. To further investigate this discordant trend, we hypothesised that tumour vasculature may play a role in delivering proteins that are not upregulated on the transcript level in the tissue itself, to the tumour tissue.…”

Dysregulation of hsa-miR-34a and hsa-miR-449a leads to overexpression of PACS-1 and loss of DNA damage response (DDR) in cervical cancer

“…While the involvement of hsa-miR-34a in cervical and other human tumors has been well established, the role of hsa-miR-449a in cancer is not well defined (25)(26)(27)(28)(29)(30)(31) . A recent report has shown that PACS-1 has a role in epigenetic regulation of gene expression (32). However, regulation of PACS-1 is not yet known.…”

PACS‐1 contains distinct motifs for nuclear‐cytoplasmic transport and interacts with the RNA‐binding protein PTBP1 in the nucleus and cytosol

“…We next hypothesized that PACS‐1 might shuttle cargo to and from the nucleus via its own nuclear trafficking. As PACS‐1 accumulates in cell nuclei during the S phase of the cell cycle to maintain chromosomal stability by regulating HDAC2 and HDAC3, we searched for potential nuclear substrates of PACS‐1 that may be involved in this process [11]. It has been previously demonstrated that a complex between HDAC2 and the polypyrimidine tract‐binding protein 1 (PTBP1) influences the interplay of histone deacetylation and RNA splicing [48,49].…”

“…PACS‐1‐WT‐GFP [5,11] and PACS‐1‐WT‐FLAG (DYKDDDDK) [16] were previously described. pDONR223‐XPO1‐WT was a gift from Jesse Boehm, William Hahn, and David Root (Addgene plasmid #81812) [17].…”

“…In addition to its cytoplasmic trafficking functions, recent reports have described nuclear roles for PACS‐1 in DNA replication and chromosome stability. PACS‐1 has been demonstrated to mediate chromosomal stability by regulating class I histone deacetylase (HDAC) 2 and 3 [11]. Emerging results also suggest that PACS‐1 nuclear localization is necessary for a proper DNA damage response [12].…”