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MBNL2 Regulates DNA Damage Response via Stabilizing p21
Jin Cai1,2, Ningchao Wang1,2, Guanglan Lin1,2
1State Key Laboratory of Chemical Oncogenomics, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China.
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.
Insights
Muscleblind-like splicing regulator 2 (MBNL2) impacts cancer cell proliferation and DNA damage response. MBNL2 depletion impairs DNA repair and senescence, promoting apoptosis, via p21 regulation.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- RNA-binding proteins regulate gene expression and are often dysregulated in cancer.
- Aberrant DNA damage response (DDR) contributes to cancer development and progression.
Purpose of the Study:
- To investigate the role of muscleblind-like splicing regulator 2 (MBNL2) in tumor cell proliferation and DNA damage response.
- To elucidate the molecular mechanisms by which MBNL2 influences cancer cell fate.
Main Methods:
- Transcriptome and gene expression analysis in MBNL2-depleted cells.
- Western blotting to assess protein levels and phosphorylation.
- Functional assays evaluating DNA damage repair, senescence, and apoptosis.
Main Results:
- MBNL2 depletion enriched the PI3K/AKT pathway and affected cyclin-dependent kinase inhibitor 1A (p21) expression.
- MBNL2 regulates p21 mRNA and protein levels independently of p53.
- MBNL2 depletion enhanced DNA damage response, indicated by increased checkpoint kinase 1 (Chk1) phosphorylation, in a p21-dependent manner.
Conclusions:
- MBNL2 plays a critical role in modulating tumor cell proliferation and DNA damage response.
- MBNL2 influences cancer cell fate post-DNA damage by regulating p21, affecting DNA repair, senescence, and apoptosis.
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