MBNL2 Regulates DNA Damage Response via Stabilizing p21.

Jin Cai,Yaou Zhang,Ningchao Wang,Guanglan Lin,Weidong Xie,Naihan Xu,Haowei Zhang

doi:10.3390/ijms22020783

Abstract

RNA-binding proteins are frequently dysregulated in human cancer and able to modulate tumor cell proliferation as well as tumor metastasis through post-transcriptional regulation on target genes. Abnormal DNA damage response and repair mechanism are closely related to genome instability and cell transformation. Here, we explore the function of the RNA-binding protein muscleblind-like splicing regulator 2 (MBNL2) on tumor cell proliferation and DNA damage response. Transcriptome and gene expression analysis show that the PI3K/AKT pathway is enriched in MBNL2-depleted cells, and the expression of cyclin-dependent kinase inhibitor 1A (p21CDKN1A) is significantly affected after MBNL2 depletion. MBNL2 modulates the mRNA and protein levels of p21, which is independent of its canonical transcription factor p53. Moreover, depletion of MBNL2 increases the phosphorylation levels of checkpoint kinase 1 (Chk1) serine 345 (S345) and DNA damage response, and the effect of MBNL2 on DNA damage response is p21-dependent. MBNL2 would further alter tumor cell fate after DNA damage, MBNL2 knockdown inhibiting DNA damage repair and DNA damage-induced senescence, but promoting DNA damage-induced apoptosis.

Highlights

We demonstrate that RNA-binding protein muscleblind-like splicing regulator 2 (MBNL2) is a novel regulator of p21
P21 is an active player in DNA damage response, and earlier studies have linked p21 induction to checkpoint kinase 1 (Chk1) inactivation
It is reported that p21 can transcriptionally repress Chk1 expression through the CDK2-pRb-E2F axis [24]

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The cyclin-dependent kinase inhibitor p21CDKN1A , known as p21Waf1/Cip , has multiple functions in cell cycle, apoptosis, DNA replication/repair and transcriptional regulation in response to a variety of stimuli, including ionizing, UV radiation and genotoxic stress [1,2]. The tumor suppressor p53 acting as the main transcriptional factor of p21, various stresses upregulating p53 activity will subsequently induce p21 expression. G1/S cell cycle progression is prevented by p21 primarily through its inhibition on CDK2 activity, which is indispensable for the phosphorylation of Rb and the consequent activation of

Methods

Results

Conclusion