PRMT5 promotes DNA repair through methylation of 53BP1 and is regulated by Src-mediated phosphorylation
Authors: Nayeon Myung
Gyoonhee Han
Doona Song
Yong Kee Kim
Mark T Bedford
Gyu-Un Bae
Su-Nam Kim
Jee Won Hwang
Journal: Communications biology (2020)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: PRMT5; phosphorylation; Src kinase; DNA repair; transcription regulation
Affiliations: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea., Natural Product Research Institute, Korea Institute of Science and Technology, Gangneung, 25451, Republic of Korea., Department of Biotechnology, Department of Biomedical Sciences, Yonsei University, Seoul, 03722, Republic of Korea., Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX, 78957, USA. ., Research Institute of Pharmaceutical Sciences, College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea. .

Abstract:  PRMT5 participates in various cellular processes, including transcription regulation, signal transduction, mRNA splicing, and DNA repair; however, its mechanism of regulation is poorly understood. Here, we demonstrate that PRMT5 is phosphorylated at residue Y324 by Src kinase, a negative regulator of its activity. Either phosphorylation or substitution of the Y324 residue suppresses PRMT5 activity by preventing its binding with the methyl donor S-adenosyl-L-methionine. Additionally, we show that PRMT5 activity is associated with non-homologous end joining (NHEJ) repair by methylating and stabilizing p53-binding protein 1 (53BP1), which promotes cellular survival after DNA damage. Src-mediated phosphorylation of PRMT5 and the subsequent inhibition of its activity during the DNA damage process blocks NHEJ repair, leading to apoptotic cell death. Altogether, our findings suggest that PRMT5 regulates DNA repair through Src-mediated Y324 phosphorylation in response to DNA damage. 

Retracted: No

PubPeer comments:
 Figure 4A. * Boxes of the same color focus attention to bands or lanes that look quite similar  , 
 For comparison: Fig 3a from [Baig et al (2019)] .  Characterization of the Chit-DNA-VL nanospheres. a Gel analysis showed the stability of the formulation .  , 
 *[left]* Figs 6A,B,C,  Results of oral administration of Chit EudDNA-VL hybrid nanospheres: A) Group 1 treated with the hybrid nanospheres showed sustained plasma elevation of the GLP1 levels than that of receiving free VL solution. B) Group 1 treated with the hybrid nanospheres showed better and consistent control of the glycemic levels than that of receiving free VL solution. C) The variations of plasma drug levels with time. *[right]* Figs 5a,b,c from [Baig et al (2019)] ,  Fig. 5 Animal studies of the Chit-DNA-VL nanospheres. b Group 1 of mice that received Chit-VLDNA nanospheres formulation successfully maintained the higher levels of GLP1 GIP in the blood for the prolonged time than the group 2 receiving free VL solution. c Group 1 of mice that received Chit-VL-DNA nanospheres formulation maintained better glycemic control for the prolonged time than the group 2 receiving blank nanospheres without VL. d Plasma drug concentration with time .  Surprisingly similar results from two different materials. Presumably different experiments, because the error bars are not the same. , 
 #1 *[left]* Third panel of Fig 4A, black white reversed for ease of comparison with *[right]* Fig 3A of [Baig et al (2019b)] ,  Physical and mechanical analysis of HPMC EC-DNA-VD nanoparticles: A) Sharp band at the top of the lanes showing resisted movement of entrapped DNA down the gel (integrity and strength of the particles) .  , 
 #3  A third sighting! Fig 5A,B,D from [Baig et al (2019b)] :  , 
 Fig 6d,  After completing the treatment duration, pancreas of the sacrificed mice was examined to observe the histology that showed no harm to the islets of Langerhans and intestinal cancers. Panels overlap.  , 
 #4  Another sighting - Fig 4A of *[left]* [Baig et al (2019a)] .  , 
 Sorry, these all belonged to a same project. Need to see if some results overlapped. Thanks for pointing out. , 
 *[left]* Fig 5A from  Vildagliptin loaded triangular DNA nanospheres coated with eudragit for oral delivery and better glycemic control in type 2 diabetes mellitus ([Baig et al 2019a] ,  FTIR of (a) formulation V3, (b) V6, (c) Eud-DNA nanospheres without VG (d) Pure VG. All the formulations containing VG showed characteristic VG peak at 1654 nm proved that VG is chemically unchanged . *[middle]* Fig 5A from the present paper,  FTIR analysis depicted chemical and physical stability visualizing all important peaks with slight shifts due to physical entrapments . The direction of the horizontal axis is not consistent across panels. *[right]* Fig 3b from  Chitosan-coated rectangular DNA nanospheres for better outcomes of anti-diabetic drug ([Baig et al 2019c] ),  FTIR analysis of the NPs showing chemical stability of the DNA and the VL with the chitosan showing all the individual peaks clearly.  The descriptions of the NPs is not entirely consistent. Using triangular vs. cubic DNA constructs as cores for the NPs seems to make no difference at all. ,