Post-Transcriptional Regulation of DNA Damage-Responsive Gene Expression

Abstract

Significance: Production of proteins requires the synthesis, maturation, and export of mRNAs before their translation in the cytoplasm. Endogenous and exogenous sources of DNA damage pose a challenge to the coordinated regulation of gene expression, because the integrity of the DNA template can be compromised by DNA lesions. Cells recognize and respond to this DNA damage through a variety of DNA damage responses (DDRs). Failure to deal with DNA damage appropriately can lead to genomic instability and cancer. Recent Advances: The p53 tumor suppressor plays a dominant role in DDR-dependent changes in gene expression, but this transcription factor is not solely responsible for all changes. Recent evidence indicates that RNA metabolism is integral to DDRs as well. In particular, post-transcriptional processes are emerging as important contributors to these complex responses. Critical Issues: Transcriptional, post-transcriptional, and translational regulation of gene expression is subject to changes in response to DNA damage. How these processes are intertwined in the unfolding of DDR is not fully understood. Future Directions: Many complex regulatory responses combine to determine cell fate after DNA damage. Understanding how transcriptional, post-transcriptional, and translational processes interdigitate to create a web of regulatory interactions will be one of the key challenges to fully understand DDRs. Antioxid. Redox Signal. 20, 640-654.

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

“…It has long been known that owing to differences in the chemistry and structure of DNA and RNA there are specific and distinct enzymes and proteins involved in DNA and RNA metabolism and maintenance pathways such as DNA repair and RNA metabolism. However, emerging evidence over the last few years suggests that the processes of DNA damage repair and RNA metabolism are more closely related than we have previously thought …”

“…In addition to BER enzymes playing a role in RNA metabolism, a number of DNA DSB repair proteins have also been implicated in these pathways, the most well characterized of these being BRCA1. Aside from its well‐characterized roles in DNA repair cell cycle checkpoint control and canonical transcriptional regulation, BRCA1 has also been shown to be involved in inhibition of transcription and RNA degradation following DNA damage, miRNA biogenesis, and mRNA splicing . Indeed, it is becoming increasingly evident that many proteins involved in DNA repair and the wider DDR pathway are also involved in the regulation of RNAs at multiple levels and vice versa a number of proteins previously thought to regulate RNA biology, e.g., SFs are now being implicated in distinct DNA repair pathways, e.g., the recently defined roles for hnRNPUL1/2 in DNA end resection during homologous recombination‐mediated DSB repair .…”

“…Moreover, the BRCA1/BARD1 complex is also responsible for ubiquitination and further degradation of RNA polymerase II in response to UV exposure, thus preventing synthesis of aberrant mRNAs. 2,[109][110][111] Taken together, this suggests that BRCA1 plays a significant role in RNA quality control following UV-induced damage and contributes to generic RNA quality control.…”

“…Interestingly, the BRCA1/BARD1 heterodimer has also been found to associate with the 50 kDa subunit of the cleavage stimulatory factor (CstF) and inhibit 3′‐end cleavage of mRNA transcripts, following UV‐induced DNA damage, thus reducing polyadenylation of the total mRNA pool (Figure ). Moreover, the BRCA1/BARD1 complex is also responsible for ubiquitination and further degradation of RNA polymerase II in response to UV exposure, thus preventing synthesis of aberrant mRNAs . Taken together, this suggests that BRCA1 plays a significant role in RNA quality control following UV‐induced damage and contributes to generic RNA quality control.…”

“…However, emerging evidence over the last few years suggests that the processes of DNA damage repair and RNA metabolism are more closely related than we have previously thought. 2,3 Specifically, certain DNA repair proteins have been shown to be involved in the RNA quality control processes, identifying damaged RNA, e.g., chemically modified or oxidized RNAs, which may lead to ribosomal malfunction, error-prone translation, and as a consequence failed protein synthesis. [4][5][6] The fact that RNA is single stranded and thus not protected by hydrogen bonds makes it extremely susceptible to base oxidation in comparison to DNA.…”