PRMT1 Is Recruited via DNA-PK to Chromatin Where It Sustains the Senescence-Associated Secretory Phenotype in Response to Cisplatin

Abstract

Graphical AbstractHighlights d Cisplatin leads to increased PRMT1 association to chromatin and H4R3 methylation d PRMT1 increase in chromatin is mediated by DNA-PK d Chromatin-associated PRMT1 sustains the transcription of SASP genes d Inhibition or genetic depletion of PRMT1 blocks SASP and sensitizes cancer cells to cisplatin

Dual role of PRMT1-dependent arginine methylation in cellular responses to genotoxic stress

“…Correlating all these facts with our observation that CDDP-induced DNA-PKcs-dependent phosphorylation of PRMT1 redirects PRMT1 activity toward histone H4 and chromatin-associated proteins at the cost of RBP methylation, 2 we envisage a model whereby cells exposed to sustained genotoxic stress activate a signaling cascade leading to the switch of PRMT1 substrate preference toward chromatin-proteins and against soluble RBPs. These events have opposite consequences on gene expression, at different levels: SASP promotes transcriptional activation in the nucleus, and SG assembly maintains the translation inhibition of stalled messenger RNAs in the cytosol ( Figure 1 ).…”

“…Recently, our team has employed an MS-based proteomic approach to investigate the role of PRMT1-mediated R-methylation in response to the genotoxic stress induced by cisplatin (CDDP). 2 We detected methylation changes in 92 R-sites on 56 proteins, with an overall methylation increase of histone H4 and chromatin-associated proteins, which was mirrored by the hypo-methylation of numerous soluble RNAbinding proteins (RBPs).…”

m 6 A deposition is regulated by PRMT1‐mediated arginine methylation of METTL14 in its disordered C‐terminal region

“…Consistent with these findings, genetic knockout and inhibition of PRMT1, which dampens METTL14 arginine methylation, also sensitized mESCs to MMC‐ and cisplatin‐induced cell death (Fig EV5E–F). Of particular relevance to this observation, Musiani and colleagues reported that, in response to cisplatin treatment, PRMT1 is recruited to chromatin to activate the transcription of genes involved in the senescence‐associated secretory phenotype by methylating histone H4 (Musiani et al , 2020). This finding suggests that PRMT1 functions through multiple pathways to promote cell survival in response to DNA damage.…”

A semi-automated organoid screening method demonstrates epigenetic control of intestinal epithelial differentiation

“…PRMT1 has a wide substrate specificity and mediates both arginine methylation of histones such as H4R3, and non-histone proteins 64,65 . Elevated PRMT1 expression is found in several cancer types and is associated with poor prognosis and chemoinsensitivity 66,67 and pharmacological PRMT inhibitors have recently gained interest as drug candidates for cancer treatment 43,45 . Targeting cancer stem cells (CSCs) in the gut comes with the challenge that following ablation of LGR5+ CSCs, LGR5-cells have the potential to de-differentiate to CSCs 68 .…”