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Connections between 3′‐end processing and DNA damage response

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Abstract The cellular DNA damage response (DDR) involves changes in the functional and structural properties of a number of nuclear proteins, resulting in a coordinated control of gene expression and DNA repair. This response includes functional interactions of the DNA repair, transcription, and RNA processing machineries. Following DNA damage, cellular levels of polyadenylated transcripts are transiently decreased and normal recovery depends on transcription‐coupled repair (TCR). In addition, DNA damage has gene‐specific effects regulating the mRNA levels of factors involved in the DDR itself at different times after the damage. The 3′‐end processing machinery, which is important in the regulation of mRNA stability, is involved in these general and gene‐specific responses to DNA damage. The role of 3′‐end processing in DDR supports the idea that the steady‐state levels of different mRNAs change upon DNA‐damaging conditions as a result of regulation of not only their biosynthesis but also their turnover. Here, we review the mechanistic connections between 3′‐end processing and DDR, and discuss the implications of deregulation of this important step of mRNA maturation in the cellular recovery after DNA‐damaging treatment. The relevance of these functional connections is illustrated by the increasing number of reports on this relatively unexplored field. Copyright © 2010 John Wiley & Sons, Ltd. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications RNA Processing > 3' End Processing RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms

General and gene‐specific effects of DNA‐damaging conditions on mRNA levels. The level of poly(A)+ mRNAs of genes not involved in the DNA damage response (DDR) decreases after DNA damage.2–6 Full recovery of mRNA levels within 6 h after the exposure correlates with the cell survival. The level of poly(A)+ mRNAs of genes involved in the DDR is down‐ or up‐regulated at different time points after DNA damage.7–10.

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Schematic diagram of the involvement of 3′‐end processing in the mRNA surveillance pathway of genes involved in DNA damage response (DDR). (A) AU‐rich elements (ARE)‐mediated destabilization prior to DNA damage. Genes involved in the early DDR are rapidly degraded in non‐treated cells. The ARE‐binding proteins (ARE‐BP) AUF1 compete with poly(A) binding protein (PABP) for binding to the poly(A) tail, destabilizing and, possibly, exposing it to deadenylases, such as poly(A)‐specific ribonuclease (PARN). Alternatively, other ARE‐BP, such as tristetraprolin (TTP) and KH‐type splicing regulatory protein (KSRP), recruit the deadenylases Ccr4 and PARN to ARE‐mRNAs and initiate deadenylation‐dependent degradation of those transcripts via the exosome. (B) ARE‐mediated stabilization during the DDR. Following DNA damage, genes involved in DDR are up‐regulated. In that scenario, the cellular levels of the ARE‐BP HuR are up‐regulated and HuR competes with AUF1 for binding to the same ARE region. This competition stabilizes the association of the PABP to the poly(A) tail. Moreover, HuR also competes with the other ARE‐BP, such as TTP and KRSP, preventing the recruitment of deadenylases to the ARE‐mRNA and the exosomal degradation.

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Model for transcriptional–3′‐end processing alternatives during the DNA damage response (DDR). The DNA damage‐induced lesions may affect the elongating RNA polymerase II–cleavage stimulation factor (RNAP II–CstF) holoenzyme in different ways. The lesion is bypassed, generating a mutant transcript. Alternatively, RNAP II stalled at sites of DNA damage can reengage in a transcriptional process. In that scenario, the BRCA1–BARD1–CstF complex reassures the correct 3′‐end processing of the nascent RNA. For some other lesions, RNAP II–CstF holoenzyme is stalled, causing premature termination or transient arrest of elongation process. BRCA1–BARD1‐containing complexes are recruited to sites of DNA repair, resulting in RNAP II ubiquitination and inhibition of transcription by degradation of RNAP II. The nascent RNA product is released and its 3′‐end processing is inhibited by both the CstF–BARD1 interaction and RNAP II degradation. This process facilitates repair by allowing access of the repair machinery to the DNA damage site, and at the same time prevents the formation of aberrantly processed mRNAs, which are eliminated by exosome‐mediated degradation in a nuclear surveillance pathway.

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RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms
RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA Processing > 3′ End Processing

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