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

Abstract

SummaryDNA 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.

PRMT5-TRIM21 interaction regulates the senescence of osteosarcoma cells by targeting the TXNIP/p21 axis

“…Thirdly, since DNA damage is the most important inducer of cellular senescence [41][42][43], we also reveal the possible mechanism demonstrating that PRMT5 plays a crucial role in regulating DSBs and DDR at either basal level or in CDDP-treated levels. This result is consistent with our recent publication reporting that PRMT5 functions as a master epigenetic activator of DDR genes [17]. These results together suggest that overexpression of PRMT5 may confer resistance of OS cells to CDDP by regulating cellular senescence, and that targeting the druggable PRMT5 in combination with chemotherapy may be utilized as a strategy for OS treatment.…”

“…In support of this finding, the expression and percentage foci of γ-H2A.X (≥ 10), a marker of DNA DSBs, as reported previously [34], were increased after the PRMT5 knockdown ( Figure 3C-3E). Since PRMT5 is reported to cause DNA damage and regulate DNA repair signaling [14][15][16][17], we sought to determine whether knockdown of PRMT5 affects DNA repair signaling in OS cells. As shown in Figure 3D-3E, the percentage of γ-H2A.X foci (≥ 10) positive cells in the scramble control (SC) group was noticeably decreased after 12 and 24 h of recovery from CDDP treatment (replacement with fresh medium), while the percentage of γ-H2A.X foci remained constant in the shP5#1 and shP5#3 groups, indicating the impairment of DNA repair signaling.…”

“…Another set of 11 OS fresh sections was used for IHC to correlate the expression of PRMT5 and Ki67 (IS62630-2, Dako, Glostrup, Denmark). Semiquantitative analysis of PRMT5 expression was performed as previously described [17].…”

“…Studies have also suggested that PRMT5 inhibition or loss-offunction impairs the DNA damage response (DDR) and induces apoptotic cell death via targeting p53, flap structure-specific endonuclease 1 (Fen1), and RuvB-like AAA ATPase 1 (RUVBL1), and Rad9 [12][13][14][15][16]. We have recently shown that PRMT5 functions as a master epigenetic activator of DDR genes, and that targeting PRMT5 by genetic knockdown or pharmacological inhibition can sensitize multiple cancer cell lines to radiation and chemotherapy [17]. PRMT5 is also responsible for regulating cellular senescence in glioblastoma neurospheres via Akt and ERK signaling [18].…”

Cancer Dependencies: PRMT5 and MAT2A in MTAP/p16-Deleted Cancers

“…Accumulating evidence in the literature demonstrates that PRMT5-mediated methylation of replication and DNA damage response (DDR) factors is critical for maintenance of genomic integrity (Clarke et al 2017, Hamard et al 2018, Owens et al 2020) (Figure 2c). In particular, methylation of POLR2A at R1810 is essential for the recruitment of the SMN complex to RNAP II transcription sites and stimulates the interaction with DNA-RNA helicase senataxin (Zhao et al 2016).…”