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Dual roles of DNA repair enzymes in RNA biology/post‐transcriptional control

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Despite consistent research into the molecular principles of the DNA damage repair pathway for almost two decades, it has only recently been found that RNA metabolism is very tightly related to this pathway, and the two ancient biochemical mechanisms act in alliance to maintain cellular genomic integrity. The close links between these pathways are well exemplified by examining the base excision repair pathway, which is now well known for dual roles of many of its members in DNA repair and RNA surveillance, including APE1, SMUG1, and PARP1. With additional links between these pathways steadily emerging, this review aims to provide a summary of the emerging roles for DNA repair proteins in the post‐transcriptional regulation of RNAs. WIREs RNA 2016, 7:604–619. doi: 10.1002/wrna.1353 This article is categorized under: RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms RNA Turnover and Surveillance > Regulation of RNA Stability RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
Cellular RNA quality control pathways. Quality control mechanisms of the nuclear and cytoplasmic RNA pools highlighting the key proteins involved in the nonsense‐mediated decay (NMD), non‐go decay (NGD), nonstop decay (NSD), rapid‐tRNA decay, and the nonfunctional RNA decay pathways.
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Functional roles of BRCA1 in RNA metabolism. (i) BRCA1 forms part of the RNA Pol II holoenzyme and through its interaction with various transcription factors (TFs) it is capable of functioning as both transcription co‐activator or co‐repressor. (ii) In response to different types of DNA damage, phosphorylated BRCA1 binds BCLAF1 which is constitutively bound to the RNA core splicing machinery. This complex then promotes the splicing and subsequent stability of BRCA1‐bound genes, many of which are involved in DDR processes such as DNA repair. (iii) In parallel, BRCA1 associates with CstF and inhibits 3′‐end cleavage of mRNA transcripts following DNA damage, thereby globally reducing mRNA synthesis and preventing the generation of aberrant transcripts. (iv) BRCA1 is also involved in pri‐miRNA biogenesis through its interaction with the DROSHA complex, thus enhancing the expression of a number of miRNAs.
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Base excision repair (BER) enzymes in RNA metabolism. (a) In the absence of stress the core BER enzymes are localized within the nucleolus, where NPM1 functions to retain them within this substructure. Here, APE1 is responsible for rRNA quality control in the nucleolus through its interaction with NPM1, whereas PARP1 regulates rDNA silencing and rRNA processing. In the nucleoplasm, APE1 exerts its endonuclease activity on damaged DNA and RNA and eliminates 3′ phosphoryl groups from RNA decay products thus contributing to the RNA degradation pathway. (i) APE1 is also able to cleave UA and CA sites within the c‐myc RNA coding region, thereby regulating its expression. (ii) Also within the nucleus, PARP1 can influence splicing efficiency through PARylation of hnRNP A2/B1. Another BER enzyme, SMUG1, shuttles from Cajal bodies to the nucleolus via its binding to DKC1 and is involved in rRNA quality control. In the cytoplasm, APE1 and PARP1 bind the small (S) and large (L) ribosomal subunit proteins indicating their possible roles in RNA metabolism within the cytoplasm. APE1 may also play a role in ribosome biogenesis through its ability to interact with the ribosomal biogenesis factors RLA and RSSA. (b) Under the stress conditions, e.g., following H2O2 treatment, the APE1 and NPM1 dissociate, and APE1 is released from the nucleolus into the nucleoplasm where it carries out its primary AP‐endonucleolytic function on damaged DNA/RNA in the nucleus. Other BER enzymes including OGG1, XRCC1, Lig I, FEN1, and PARP1 are also released from the nucleolus to carry out their various BER functions on damaged DNA. Additionally, PARP1 contributes to the global inhibition of mRNA synthesis through PARylation of the PAP (poly‐A polymerase) enzyme.
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RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA Turnover and Surveillance > Regulation of RNA Stability
RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms

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