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

Oncogene volume 39, pages 2583–2596 (2020)Cite this article

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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.

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Fig. 1: PACS-1 nuclear accumulation increases during cell cycle progression and its deficiency induces replication stress and cell death.
Fig. 2: PACS-1 regulates replication progression during normal and perturbed conditions and its deficiency leads to genomic instability.
Fig. 3: PACS-1 localizes to chromatin and regulates the stability of HDAC2 and HDAC3 proteins.
Fig. 4: PACS-1 binds to HDAC2 and HDAC3 proteins and regulates their stabilities.
Fig. 5: FBR region of PACS-1 is essential for its interaction with HDACs.
Fig. 6: PACS-1 interactions with HDACs are distinct from its cytosolic TGN functions.
Fig. 7: PACS-1 promotes malignant behavior of cancer cells and a poor prognostic marker.

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Acknowledgements

We thank Steve McClellan, Mitchell Cancer Institute for flow cytometry. This work is supported by grants from Abraham Mitchell Cancer Research Scholar Endowment grant, and partly by NIH grants R01GM098956 and R01CA219187 to KP, the NIH grants DK114855 and DK112844 to GT, the NIH grant R01GM108648 and DOD BRCP Breakthrough Award BC151728 to AV.

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Authors and Affiliations

  1. Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Centre, Lubbock, TX, 79430, USA

    Chinnadurai Mani & Komaraiah Palle

  2. Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA

    Chinnadurai Mani, Kaushlendra Tripathi, David W. Clark, Joel F. Andrews & Komaraiah Palle

  3. Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA

    Shan Luan & Gary Thomas

  4. University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15239, USA

    Shan Luan & Gary Thomas

  5. University of Pittsburgh School of Medicine, 5117 Centre Avenue, Pittsburgh, PA, 15213, USA

    Shan Luan & Gary Thomas

  6. Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA

    Alessandro Vindigni

  7. Department of Surgery, Texas Tech University Health Sciences Centre, Lubbock, TX, 79430, USA

    Komaraiah Palle

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Mani, C., Tripathi, K., Luan, S. et al. The multifunctional protein PACS-1 is required for HDAC2- and HDAC3-dependent chromatin maturation and genomic stability. Oncogene 39, 2583–2596 (2020). https://doi.org/10.1038/s41388-020-1167-x

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