MDM4 regulation by the let‐7 miRNA family in the DNA damage response of glioma cells. Issue 15 (27th May 2015)

• Record Type: Journal Article
• Authors: Xie, Chen; Chen, Wei; Zhang, Mengdie; Cai, Qiuxian; Xu, Weiyi; Li, Xiaodi; Jiang, Songshan
• Is Part Of: FEBS letters. Volume 589:Issue 15(2015)
• Page Start: 1958
• Page End: 1965
• Publication Date: 2015-05-27
• Subjects: MicroRNA let-7 -- DNA damage -- MDM4 -- Coding DNA sequence -- Glioma; Biochemistry -- Periodicals; Biophysics -- Periodicals; Molecular biology -- Periodicals; Biochimie -- Périodiques; Biochemistry; Biophysics; Molecular biology; Periodicals; 572.05
• DOI: 10.1016/j.febslet.2015.05.030
• Languages: English
• ISSNs: 0014-5793

Abstract

Abstract : Despite extensive investigation into the role of let‐7 miRNAs in pathological tumor processes, their involvement in the DNA damage response remains unclear. Here we show that most let‐7 family members down‐regulate MDM4 expression via binding to MDM4 mRNA at a conserved DNA sequence. Expression of exogenous let‐7 miRNA mimics decreased MDM4 protein but not mRNA levels. Several DNA damage reagents increased let‐7 expression, thereby decreasing MDM4 protein levels in glioma cells. Inhibition of endogenous let‐7 with antisense RNAs rescued MDM4 protein levels with or without MG132, a proteasome‐dependent degradation inhibitor. An MDM4 mutation identified in a glioma patient was associated with loss of the putative MDM4 target site. Therefore, let‐7 binding to MDM4 is implicated in the DNA damage response. Abstract : Let‐7 represses MDM4 expression by directly binding to its coding sequence. DNA damage induces let‐7 expression with subsequent decrease in MDM4. A mutation found in glioma patients may disrupt the relationship between let‐7 and MDM4. Binding of let‐7 to MDM4 is implicated in the DNA damage response.