Cai Jin, Wang Ningchao, Lin Guanglan, Zhang Haowei, Xie Weidong, Zhang Yaou, Xu Naihan
State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China.
Open FIESTA Center, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China.
Int J Mol Sci. 2021 Jan 14;22(2):783. doi: 10.3390/ijms22020783.
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 (p21) 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.
RNA结合蛋白在人类癌症中经常失调，并能够通过对靶基因的转录后调控来调节肿瘤细胞增殖以及肿瘤转移。异常的DNA损伤反应和修复机制与基因组不稳定和细胞转化密切相关。在此，我们探讨RNA结合蛋白类肌肉盲剪接调节因子2（MBNL2）在肿瘤细胞增殖和DNA损伤反应中的作用。转录组和基因表达分析表明，PI3K/AKT信号通路在MBNL2缺失的细胞中富集，MBNL2缺失后细胞周期蛋白依赖性激酶抑制剂1A（p21）的表达受到显著影响。MBNL2调节p21的mRNA和蛋白水平，这与其经典转录因子p53无关。此外，MBNL2的缺失增加了检查点激酶1（Chk1）丝氨酸345（S345）的磷酸化水平和DNA损伤反应，并且MBNL2对DNA损伤反应的影响是p21依赖性的。DNA损伤后，MBNL2会进一步改变肿瘤细胞的命运，敲低MBNL2会抑制DNA损伤修复和DNA损伤诱导的衰老，但会促进DNA损伤诱导的凋亡。
