PRMT5 Cooperates with pICln to Function as a Master Epigenetic Activator of DNA Double-Strand Break Repair Genes
Jake L. Owens,
Elena Beketova,
Sheng Liu,
Samantha L. Tinsley,
Andrew M. Asberry,
Xuehong Deng,
Jiaoti Huang,
Chenglong Li,
Jun Wan,
Chang-Deng Hu
Affiliations
Jake L. Owens
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA
Elena Beketova
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
Sheng Liu
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
Samantha L. Tinsley
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
Andrew M. Asberry
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
Xuehong Deng
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA
Jiaoti Huang
Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA
Chenglong Li
Department of Medicinal Chemistry, University of Florida College of Pharmacy, Gainesville, FL 32610, USA
Jun Wan
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; Corresponding author
Chang-Deng Hu
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; Corresponding author
Summary: 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. : Molecular Genetics; Molecular Biology; Molecular Mechanism of Gene Regulation Subject Areas: Molecular Genetics, Molecular Biology, Molecular Mechanism of Gene Regulation
