This Title All WIREs
How to cite this WIREs title:
Impact Factor: 9.957

Connections between 3′ end processing and DNA damage response: Ten years later

Full article on Wiley Online Library:   HTML PDF

Can't access this content? Tell your librarian.

Abstract Ten years ago we reviewed how the cellular DNA damage response (DDR) is controlled by changes in the functional and structural properties of nuclear proteins, resulting in a timely coordinated control of gene expression that allows DNA repair. Expression of genes that play a role in DDR is regulated not only at transcriptional level during mRNA biosynthesis but also by changing steady‐state levels due to turnover of the transcripts. The 3′ end processing machinery, which is important in the regulation of mRNA stability, is involved in these gene‐specific responses to DNA damage. Here, we review the latest mechanistic connections described between 3′ end processing and DDR, with a special emphasis on alternative polyadenylation, microRNA and RNA binding proteins‐mediated deadenylation, and discuss the implications of deregulation of these steps in DDR and human disease. This article is categorized under: RNA Processing > 3′ End Processing RNA‐Based Catalysis > Miscellaneous RNA‐Catalyzed Reactions RNA in Disease and Development > RNA in Disease
Factor flux before and after the introduction of genotoxic stress. Top: In nonstress conditions, promoter‐proximal poly(A) signals are suppressed by the “telescripting” effect of U1 snRNA in a 5′→3′ direction, including both intronic and proximal 3′ UTR poly(A) signals (Berg et al., ). The CpA machinery operates unhindered as a multitude of core and auxiliary factors function to process the precursor mRNA, including PAP and CstF‐50 (Y. Shi et al., ). Bottom: Upon occurrence and recognition of genotoxic stress, the ribonucleoprotein components of CpA function are altered, as U1 snRNA levels are decreased, allowing for recognition of specific promoter‐proximal poly(A) signals (Devany et al., ). Recruitment of BRCA1/BARD1/p53 complex(es) takes place, inhibiting CpA via CstF‐50 (Kleiman & Manley, ), and activating deadenylation through factors such as PARN (Devany, Zhang, Park, Tian, & Kleiman, ). A number of CpA factors undergo DNA‐PK‐ and/or PARP1‐mediated posttranslational modifications, affecting their activity (Jungmichel et al., ). Star‐PAP is also recruited to certain stress‐response genes (W. Li et al., ) as well as poly(U) polymerases in the cytoplasm during apoptosis (Thomas et al., ). There are also potential mRNA methylation events and guanines added to the mRNA 3′ ends (Lim et al., ), though these are yet to be described in DDR context. The role of noncoding RNAs in this regulation is also a nascent field (Huang et al., ). CpA, cleavage and polyadenylation; DDR, DNA damage response; PAP, poly(A) polymerase; PARN, poly(A)‐specific ribonuclease
[ Normal View | Magnified View ]
Categories of events and pathways involved at the intersection of mRNA 3′ end processing and DNA damage response, as discussed in this review
[ Normal View | Magnified View ]
TP53 mRNA post‐transcriptional regulation before and after DNA damage. Under non‐stress conditions, multiple different miRNAs as part of Ago2‐containing miRISC complex possess binding sites for TP53 3′ UTR, recruiting deadenylases, such as PARN (Cevher et al., ), leading to decay or miRNA‐mediated translational repression (Devany et al., ). HuR and other RBPs are phosphorylated by cellular kinases (Kim, Abdelmohsen, & Gorospe, 2010), preventing binding to mRNA. Under stress conditions, HuR and Wig1 are dephosphorylated by DDR kinases allowing their binding to ARE‐sequences present in mRNA targets (Mukherjee et al., ; Vilborg et al., ). Steric overlap of miRNA seed sequence with ARE‐sequence prevents Ago2/PARN association, leading to increase mRNA stability and translational capacity (Mukherjee et al., ; X. Zhang et al., ). Concomitantly, global inhibition of CpA by CstF‐50/BRCA1/BARD1 (Kleiman & Manley, , ) is overcome in part through functional complementation of RNA helicase DHX36 and factor hnRNP H/F binding to G‐quadruplex structure downstream of TP53 cleavage site (Newman et al., ). ARE, AU‐rich element; CpA, cleavage and polyadenylation; DDR, DNA damage response; PARN, PARN, poly(A)‐specific ribonuclease; RBPs, RNA binding proteins
[ Normal View | Magnified View ]

Browse by Topic

RNA in Disease and Development > RNA in Disease
RNA-Based Catalysis > Miscellaneous RNA-Catalyzed Reactions
RNA Processing > 3′ End Processing

Access to this WIREs title is by subscription only.

Recommend to Your
Librarian Now!

The latest WIREs articles in your inbox

Sign Up for Article Alerts