Diverse functions of deadenylases in DNA damage response and genomic integrity

Abstract

DNA damage response (DDR) is a coordinated network of diverse cellular processes including the detection, signaling, and repair of DNA lesions, the adjustment of metabolic network and cell fate determination. To deal with the unavoidable DNA damage caused by either endogenous or exogenous stresses, the cells need to reshape the gene expression profile to allow efficient transcription and translation of DDR-responsive messenger RNAs (mRNAs) and to repress the nonessential mRNAs. A predominant method to adjust RNA fate is achieved by modulating the 3'-end oligo(A) or poly(A) length via the opposing actions of polyadenylation and deadenylation. Poly(A)-specific ribonuclease (PARN) and the carbon catabolite repressor 4 (CCR4)-Not complex, the major executors of deadenylation, are indispensable to DDR and genomic integrity in eukaryotic cells. PARN modulates cell cycle progression by regulating the stabilities of mRNAs and microRNA (miRNAs) involved in the p53 pathway and contributes to genomic stability by affecting the biogenesis of noncoding RNAs including miRNAs and telomeric RNA. The CCR4-Not complex is involved in diverse pathways of DDR including transcriptional regulation, signaling pathways, mRNA stabilities, translation regulation, and protein degradation. The RNA targets of deadenylases are tuned by the DDR signaling pathways, while in turn the deadenylases can regulate the levels of DNA damage-responsive proteins. The mutual feedback between deadenylases and the DDR signaling pathways allows the cells to precisely control DDR by dynamically adjusting the levels of sensors and effectors of the DDR signaling pathways. Here, the diverse functions of deadenylases in DDR are summarized and the underlying mechanisms are proposed according to recent findings. This article is categorized under: RNA Processing > 3' End Processing RNA in Disease and Development > RNA in Disease RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms.

Keywords: CCR4-Not complex; DNA damage response; deadenylase; genomic integrity; poly(A)-specific ribonuclease.