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PMID: 31884170 Published · ppublish English Journal Article

PRMT5 Cooperates with pICln to Function as a Master Epigenetic Activator of DNA Double-Strand Break Repair Genes.

iScience ·Vol. 23 ·No. 1 ·2020-01-24 ·Pages 100750

Owens JL, Beketova E, Liu S, Tinsley SL, Asberry AM, Deng X, Huang J, Li C, Wan J, Hu CD

Abstract

DNA double-strand break (DSB) repair is critical for cell survival and genome integrity. Upon recognition of DSBs, repair proteins are transiently upregulated to facilitate repair through homologous recombination (HR) or non-homologous end joining (NHEJ). We present evidence that PRMT5 cooperates with pICln to function as a master epigenetic activator of DNA damage response (DDR) genes involved in HR, NHEJ, and G2 arrest (including RAD51, BRCA1, and BRCA2) to upregulate gene expression upon DNA damage. Contrary to the predominant role of PRMT5 as an epigenetic repressor, our results demonstrate that PRMT5 and pICln can activate gene expression, potentially independent of PRMT5's obligate cofactor MEP50. Targeting PRMT5 or pICln hinders repair of DSBs in multiple cancer cell lines, and both PRMT5 and pICln expression positively correlates with DDR genes across 32 clinical cancer datasets. Thus, targeting PRMT5 or pICln may be explored in combination with radiation or chemotherapy for cancer treatment.

Keywords
Molecular Biology Molecular Genetics Molecular Mechanism of Gene Regulation
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Owens Jake L
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
Beketova Elena
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA; Purdue University Interdisciplinary Life Sciences Graduate Program, Purdue University, West Lafayette, IN 47907, USA.
Liu Sheng
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; The Indiana University Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, IN 46202, USA.
Tinsley Samantha L
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA; Purdue University Interdisciplinary Life Sciences Graduate Program, Purdue University, West Lafayette, IN 47907, USA.
Asberry Andrew M
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA; Purdue University Interdisciplinary Life Sciences Graduate Program, Purdue University, West Lafayette, IN 47907, USA.
Deng Xuehong
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
Huang Jiaoti
Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA.
Li Chenglong
Department of Medicinal Chemistry, University of Florida College of Pharmacy, Gainesville, FL 32610, USA.
Wan Jun
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; The Indiana University Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, IN 46202, USA; The Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of BioHealth Informatics, Indiana University School of Informatics and Computing, Indiana University - Purdue University Indianapolis, Indianapolis, IN 46202, USA. Electronic address: junwan@iu.edu.
Hu Chang-Deng
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA; Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA. Electronic address: hu1@purdue.edu.
Conflict of Interest

Declaration of Interests The authors declare no competing interests.

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Article Info
Journal
iScience
Abbr.
iScience
ISSN
2589-0042
DOI
10.1016/j.isci.2019.100750
Email
junwan@iu.edu
hu1@purdue.edu
Published
2020-01-24
Epub
2019-00-29
Pages
100750
Language
English
Region
United States
NLM ID
101724038
PMCID
PMC6941881
Grants
NIGMS NIH HHS · T32 GM125620 · United States
NCI NIH HHS · P30 CA082709 · United States
NCATS NIH HHS · UL1 TR001108 · United States
NCI NIH HHS · R01 CA212403 · United States
NCATS NIH HHS · TL1 TR001107 · United States
NCI NIH HHS · P30 CA023168 · United States
NCATS NIH HHS · UL1 TR002529 · United States
NCATS NIH HHS · TL1 TR002531 · United States
External Links
PubMed source DOI: 10.1016/j.isci.2019.100750 PMC Full Text View journal details
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