PRMT1-dependent methylation of BRCA1 contributes to the epigenetic defense of breast cancer cells against ionizing radiation

María F Montenegro,Luis Sánchez-Del-Campo,Antonio Piñero-Madrona,Rebeca González-Guerrero,José Neptuno Rodríguez-López,Juan Cabezas-Herrera

doi:10.1038/s41598-020-70289-3

María F Montenegro, Luis Sánchez-Del-Campo + Show 4 more

Open Access

https://doi.org/10.1038/s41598-020-70289-3

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Abstract

The therapeutic effect of irradiation is thought to come from DNA damage that affects rapidly proliferating cancer cells; however, resistant cells rapidly initiate mechanisms to repair such damage. While DNA repair mechanisms responsible for cancer cell survival following DNA damage are understood, less is known about the epigenetic mechanisms resulting in resistance to radiotherapy. Although changes in DNA methylation are related to mechanisms of long-term resistance, it is more likely that the methylation state of a series of proteins could be responsible for the first-line of defense of cancer cells against irradiation. In this study, we observed that irradiation of breast cancer cells was accompanied by an overproduction in S-adenosylmethionine, which increases the activity of cellular methylases. We found that by activating PRMT1, irradiation triggers a BRCA1-dependent program that results in efficient DNA repair and inhibition of apoptosis. Depletion of PRMT1 in irradiated cells resulted in a switch of BRCA1 functions from repair and survival in the nucleus to activation of cell death signals in the cytoplasm. We conclude that by modulating the cellular localization of BRCA1, PRMT1 is an important regulator of the oncogenic functions of BRCA1, contributing to the epigenetic defense of breast cancer cells against ionizing radiation.

Highlights

The therapeutic effect of irradiation is thought to come from DNA damage that affects rapidly proliferating cancer cells; resistant cells rapidly initiate mechanisms to repair such damage
Because BRCA1 needs to be translocated into the nucleus to perform its DNA-repairing functions, these results indicated that methylation of BRCA1 by PRMT1 may be necessary to activate BRCA1-dependent DNA repair in breast cancer cells that are subjected to ionizing radiation (IR)
Since PRMT1 coimmunoprecipitated with BRCA1 (Fig. 1A), whether methylation of BRCA1 after IR was dependent on PRMT1 was confirmed by immunoprecipitation assays in MCF7 and MDA-MB-231 cells

Summary

Introduction

The therapeutic effect of irradiation is thought to come from DNA damage that affects rapidly proliferating cancer cells; resistant cells rapidly initiate mechanisms to repair such damage. PRMT1 is a key posttranslational modification factor in the DNA damage response (DDR) pathway in proliferating mammalian cells In this sense, recent investigations demonstrated that methylation of BRCA1 by PRMT1 influenced its transcriptional cofactor functions[11]. The results indicated that tumor cells could quickly react to genotoxic stress by an mTOR-dependent pathway that reprogram the bioenergetics of the cells switching from aerobic glycolysis to mitochondrial oxidative phosphorylation In addition to this metabolic change, epigenetic events have been shown to be crucial for damage repair and survival after exposure to IR. We identified PRMT1 as a methyltransferase that contributes to the epigenetic defense of cancer cells against ionizing radiation These results could have clinical implications because we identified a targeted epigenetic network that controls DNA repair mechanisms but is connected to suppressing apoptotic pathways in response to radiotherapy

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