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Diverse functions of deadenylases in DNA damage response and genomic integrity

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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
A simplified model for the switch of PARN targets from DDR‐responsive genes under nonstressed conditions to nonresponsive genes under genotoxic conditions. (a) Under nonstressed conditions, PARN is recruited to the DDR‐responsive mRNAs by trans‐acting factors that recognizing the cis‐acting elements located on the 3´‐UTR of the mRNAs. The most well‐defined pairs are ARE and ARE‐BPs. Meanwhile, miRISC can also be loaded to the miRNA‐recognition sites and amplifies the deadenylation activity of PARN. DNA damage activates ATM/ATR and downstream kinases, which phosphorylate trans‐acting factors and PARN. The alteration in phosphorylation status switches the affinity of trans‐acting factors to bind with the cis‐acting elements and thereby expelled PARN from the DDR‐responsive mRNAs to avoid deadenylation. (b) PARN activity towards the nonresponsive house‐keeping mRNAs are inhibited by PARN‐binding proteins under the nonstressed conditions. DNA damage activates MK2 to phosphorylate PARN, which releases PARN from the inhibitory binding partners. The released PARN is then recruited by the other trans‐acting factors to activate the deadenylation of nonresponsive mRNAs. ARE, AU‐rich element; ARE‐BPs, ARE‐binding proteins; DDR, DNA damage response; mRNA, messenger RNAs; MK2, MAPKAP kinase 2; ncRNA, noncoding RNAs; PARN, poly(A)‐specific ribonuclease; UTR, untranslational region
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Diverse subcellular localizations of PARN. PARN is enriched in the nucleoli and Cajal bodies under nonstressed conditions. PARN also distributes in the nucleoplasm, cytosol and ER. Some DNA damage reagents can induce translocation of the nuclear PARN to the cytoplasm. During DDR, MK2 phosphorylates PARN to dissociate the ER‐anchored PARN. PARN translocation reflects the cellular requirement of stage‐specific actions to reshape the mRNA and ncRNA profiles. (Modified with permission from Duan et al. (2020). DDR, DNA damage response; mRNA, messenger RNAs; MK2, MAPKAP kinase 2; ncRNA, noncoding RNAs; PARN, poly(A)‐specific ribonuclease
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A proposed model of stage‐specific switch of the subset of mRNA targets achieved by diverse combinations of cis‐acting elements, adaptor proteins and regulators of adaptor proteins as well as different compositions of the CCR4‐Not complex. This stage‐specific switch can occur during oocyte maturation, early development as well as DDR. A1 and An represent RBPs that recruit the CCR4‐Not complex at stage 1 and stage n. B1, B1‐BP, Bn and Bn‐BP represent RBPs and RBP‐binding proteins that cooperatively recruit the CCR4‐Not complex at stage 1 and stage n. DDR, DNA damage response; mRNA, messenger RNAs; cRNA, noncoding RNAs; PARN, poly(A)‐specific ribonuclease
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A simplified model for the general action of PARN on the biogenesis and quality control of various ncRNAs. PARN degrades 3′‐extensions encoded in the genome of some ncRNAs. PARN competes with terminal nucleotidyltransferases such as PAPD5 to avoid the addition of nontemplated nucleotides, which generally trigger the degradation of ncRNAs. During DDR, PARN switches the subset of ncRNA targets by phosphorylation‐triggered alterations in binding partners. DDR, DNA damage response; mRNA, messenger RNAs; ncRNA, noncoding RNAs; PARN, poly(A)‐specific ribonuclease
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A proposed model of the mutual feedback between the CCR4‐Not complex and signaling pathways. On one hand, the CCR4‐Not complex is downstream of signaling pathways. Either the CCR4‐Not complex components or the adaptor proteins can be phosphorylated by kinases of the signaling pathways. Phosphorylation‐induced alterations in protein‐interacting network switches the subset of mRNA targets to respond to the signals, and in this way the CCR4‐Not complex acts as the effector of the signaling pathways. On the other hand, the CCR4‐Not complex monitors replication, transcription and translation stresses like a sensor and transmits the stress signals by modifying the protein levels of the corresponding signaling pathways via ubiquitination‐directed degradation, translation repression and/or mRNA degradation. Furthermore, in some cases, the CCR4‐Not complex can target its upstream kinase, either at the mRNA or protein level, and thereby balances the signaling transduction and gene expression status. CCR4, carbon catabolite repressor 4; DDR, DNA damage response; mRNA, messenger RNAs
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A summary of the functions of the CCR4‐Not complex in DDR and maintenance of genomic integrity. CCR4, carbon catabolite repressor 4; DDR, DNA damage response; NPC, nuclear pore complex; TF, transcription factor
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RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms
RNA in Disease and Development > RNA in Disease
RNA Processing > 3′ End Processing

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