Modulation of the tumor suppressor p53 pathway by arginine methyltransferases

1564 The tumor suppressor p53 is the most commonly mutated gene in human cancer. As a transcription factor, p53 plays an essential role in the induction of cellular processes such as cell cycle arrest, apoptosis, and senescence in response to stress signals. Post-translational modifications and interaction with cofactors are the primary mediators of p53 stabilization and activation upon cellular stresses. Protein arginine methyltransferases (PRMTs) are known to methylate histones and many cellular proteins involved in diverse processes such as DNA repair, transcription, and RNA processing. Here, we showed that inhibition of protein methyltransferases, especially arginine methyltransferases, prevents the induction of p21 and MDM2 as well as the repression of ECT2 in response to DNA damage, in a p53-dependent manner. To identify which arginine methyltransferase is required for p53 transcriptional activity, we generated multiple cell lines in which PRMT1, CARM1, or PRMT5 are inducibly knocked down by the tetracycline-inducible shRNA expression system in MCF7 breast adenocarcinoma cells. We found that PRMT1 and/or CARM1 knockdown has a limited effect on cell proliferation. In addition, PRMT1 and CARM1 deficiency do not have an effect on p53 stabilization and transcriptional activity upon DNA damage or MDM2 inhibition. However, we found that PRMT5 is required for cell proliferation. In addition, we showed that deficiency in PRMT5 leads to cell cycle arrest in G1. Interestingly, we also found that PRMT5 knockdown attenuates p53 stabilization upon DNA damage, leading to a decreased induction of MDM2 and p21. Taken together, we uncovered that the arginine methyltransferase family member PRMT5 has a pro-survival function and also acts as a novel modulator of p53 transcriptional activity.