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Review
. 2021 Dec 22;23(1):96.
doi: 10.3390/ijms23010096.

AU-Rich Element RNA Binding Proteins: At the Crossroads of Post-Transcriptional Regulation and Genome Integrity

Ahmed Sidali  1 , Varsha Teotia  1 , Nadeen Shaikh Solaiman  1 , Nahida Bashir  1 , Radhakrishnan Kanagaraj  1   2 , John J Murphy  1 , Kalpana Surendranath  1
Affiliations
Review

AU-Rich Element RNA Binding Proteins: At the Crossroads of Post-Transcriptional Regulation and Genome Integrity

Ahmed Sidali et al. Int J Mol Sci. .

Abstract

Genome integrity must be tightly preserved to ensure cellular survival and to deter the genesis of disease. Endogenous and exogenous stressors that impose threats to genomic stability through DNA damage are counteracted by a tightly regulated DNA damage response (DDR). RNA binding proteins (RBPs) are emerging as regulators and mediators of diverse biological processes. Specifically, RBPs that bind to adenine uridine (AU)-rich elements (AREs) in the 3' untranslated region (UTR) of mRNAs (AU-RBPs) have emerged as key players in regulating the DDR and preserving genome integrity. Here we review eight established AU-RBPs (AUF1, HuR, KHSRP, TIA-1, TIAR, ZFP36, ZFP36L1, ZFP36L2) and their ability to maintain genome integrity through various interactions. We have reviewed canonical roles of AU-RBPs in regulating the fate of mRNA transcripts encoding DDR genes at multiple post-transcriptional levels. We have also attempted to shed light on non-canonical roles of AU-RBPs exploring their post-translational modifications (PTMs) and sub-cellular localization in response to genotoxic stresses by various factors involved in DDR and genome maintenance. Dysfunctional AU-RBPs have been increasingly found to be associated with many human cancers. Further understanding of the roles of AU-RBPS in maintaining genomic integrity may uncover novel therapeutic strategies for cancer.

Keywords: Adenine-Uridine rich element; DNA damage response; RNA binding proteins; cancer; genome stability; oncogenes; post-transcriptional regulation; replication stress; tumour suppressors.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
AU-RBPs at the nexus of the double strand break repair. DSBs initiated by endogenous or exogenous sources (red bolt) primarily lead to the activation of ATM. Initially, exposed DNA ends are sensed by the Mre11-Rad50-Nbs1 (MRN) complex, a key regulator of ATM activation, resulting in phosphorylation (+P) and activation of ATM. Activated ATM, phosphorylates downstream effectors CHK2, p53, BRCA1, and 53BP1 mediating cell-cycle arrest, apoptosis, and DNA repair through homologous recombination (HR) or non-homologous end-joining (NHEJ) pathways. ATM-directed phosphorylation of histone 2AX at serine 139 (γH2AX) is recognised by MDC1, resulting in wide-spread activation of γH2AX over chromatin domains recruiting DNA repair factors at the site of DNA damage. AU-RBPs have been reported to form direct interactions, such as, KHSRPs phosphorylation by ATM early in the DSB pathway promoting KHSRP’s role in pri-miRNA processing. AU-RBP HuR is phosphorylated by CHK2 promoting destabilsation of target mRNA sirt1. Alternatively, HuR may also stabilise p53 mRNA, promoting p53 translation to coordinate the DDR. AU-RBP AUF1 has been shown to associate with DSB repair through HR and may also interact with proteins involved in NHEJ, such as XRCC5 and XRCC6 (discussed below).
Figure 2
Figure 2
AU-RBPs at the nexus of the replication stress response. The eukaryotic replicative helicase complex unwinds parental DNA enabling replication of the leading and lagging strands by DNA polymerase Pol ε and Pol δ respectively. Replication stress can result in stalled replication fork progression (orange bolt) leading to stretches of single-stranded DNA (ssDNA) as the DNA continues to unwind. ssDNA becomes bound and protected by the ssDNA binding protein replication protein A (RPA), initiating ATR kinase recruitment. ATR recruitment is facilitated by interactions with ATR interacting protein (ATRIP), resulting in downstream activation of factors involved in the resolution of compromised replication forks. For ATR to phosphorylate its primary target, the master regulator CHK1 and CLASPIN must bind to RPA enabling phosphorylation of CHK1 at serine residues 317 and 345. This is accompanied by the phosphorylation of H2A histone family member x (H2AX) at serine 139 (γH2AX) early in the replication stress response. Activation of CHK1 ensures faithful restoration of the replication fork by initiating cell-cycle arrest, preventing origin firing, promoting fork stabilisation, DNA repair, and fork restart. The AU-RBP ZFP36 has been reported to be a key component in mediating faithful activation of CHK1 by ATR, by increasing the stability of CLASPIN mRNA. AU-RBP TIAR has been linked to arresting cell cycle at the G2/M border in response to replication stress by attenuating CDK1 in G2/M transition granules (GMGs) inhibiting entry into mitosis (discussed below).
Figure 3
Figure 3
AU-RBPs exhibit post-translational modifications in response to genotoxic stress. Genotoxic stress results in post-translational modifications of AU-RPBs influencing their activity. The AU-RBP HuR is targeted for phosphorylation by CHK2 resulting in its dissociation from SIRT1 inhibiting SIRT1 expression and increasing cell survival. When CHK2 mediated phosphorylation of HuR is blocked, HuR remains bound to SIRT1 resulting in increased SIRT1 expression and decreasing cell survival. KSHRP is phosphorylated by ATM promoting its role in Pri-miRNA processing and miRNA biogenesis, which may have a role in the DDR. Concomitant phosphorylation of AU-RBP TIAR by p38 and PARN and hnRNP A0 by MK2 is involved in TIARs dissociation from Gadd45α resulting in Gadd45α’s stabilization and increasing GADD45α expression. Polyubiquitination of ZFP36L2 by ZYG11B-E3 ubiquitin ligase complex regulate ZFP36L2 expression levels ensuring its degradation. Genotoxic stress increases ZFP36L2 resulting in S-phase arrest which may be attributed to a reduction in polyubiquitination of ZFP36L2.
Figure 4
Figure 4
Subcellular environment dictates nucleocytoplasmic shuttling of AU-RBPs. In the nucleus, interaction of AU-RBP ZFP36 with retroviral transcriptional activator Tax protein results in shuttling of ZFP36 inside the nucleus and indirectly increase of TNFα mRNA in the cytoplasm. AU-RBP HuR translocates to cytoplasm in response to DNA-damage, resulting HuR binding and stabilisation of its mRNA targets including TFAM, PARG, CDKN1A. Bold black arrows indicate mobility of the AU-RBPs across the cellular compartments shown and red arrows indicate increased stability of the mRNAs.
Figure 5
Figure 5
Potential roles of AU-RBPs in preventing R-loop formation in response to replication stress. During the process of transcription by RNA polymerase II (RNA pol II), the nascent RNA is prevented from hybridizing with the template strand DNA strand (RNA: DNA hybrid) in the presence of AUF1 and possibly other AU-RBPs. Therefore preventing the formation of R-loops that cause replication stress and DNA damage. In the absence of AUF1 and possibly other AU-RBPs the nascent RNA can hybridise with the template strand and displace the non-template strand into a long stretch of ssDNA forming an R-loop structure. Unresolved R-loops can cause transcription and replication fork collisions, resulting in increased replication stress and DNA damage that compromise genomic instability.
Figure 6
Figure 6
AU-RBPs are aberrantly expressed in various kinds of cancer, where AUF1, HuR, KHSRP and ZFP36L2 are found to be mostly upregulated and TIA1, ZFP36 and ZFP36L1 are found to be downregulated in breast, lung and liver cancers.
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