Essential role for the interaction between hnRNP H/F and a G quadruplex in maintaining p53 pre-mRNA 3′-end processing and function during DNA damage

Abstract

Following DNA damage, mRNA 39-end formation is inhibited, contributing to repression of mRNA synthesis. Here we investigated how DNA-damaged cells accomplish p53 mRNA 39-end formation when normal mechanisms of pre-mRNA 39-end processing regulation are inhibited. The underlying mechanism involves the interaction between a G-quadruplex structure located downstream from the p53 cleavage site and hnRNP H/F. Importantly, this interaction is critical for p53 expression and contributes to p53-mediated apoptosis. Our results uncover the existence of a specific rescue mechanism of 39-end processing regulation allowing stress-induced p53 accumulation and function in apoptosis.

A recently evolved class of alternative 3′-terminal exons involved in cell cycle regulation by topoisomerase inhibitors

“…Another mechanism regulating intronic polyA sites is repression by the U1 snRNA, but again, DOXO effects on ALEs were much more specific than those of U1 11,12 . Finally, as hnRNP H/F proteins protect p53 transcripts against polyA repression by DNA damage 18 , they might also contribute to ALE regulation. Altogether, while our data reveal a mechanism of internal ALE repression by TOP inhibitors through HuR, it is likely that DNAdamaging agents can regulate other polyA sites by other mechanisms.…”

“…2f). Fifth, DOXO and CPT increased the use of the E13 polyA site relative to the E12 polyA site, as shown by quantifying in nuclear RNA fractions, the transcripts upstream and downstream of each polyA site 18 ( Supplementary Fig. 2g).…”

“…These responses involve a partial repression of gene expression, accompanied by the selective upregulation of genes involved in DNA repair, cell cycle arrest and eventually cell death, which is coordinated in a large part by the p53 transcription factor. Likewise, UV irradiation partially inhibits cleavage/polyadenylation 17 , but p53 transcripts escape such repression 18 . Several genes involved in the DNA damage response, such as MDM2 that encodes the main repressor of p53, are regulated at the splicing level in response to genotoxic agents 16 .…”

DNA damage induces targeted, genome-wide variation of poly(A) sites in budding yeast

“…In mammalian cells, specific RNA binding proteins have been found to promote use of alternative poly(A) sites in some genes (for review, see Di Giammartino et al 2011;Shi 2012) or to prevent the suppression of TP53 mRNA polyadenylation after DNA damage (Decorsiere et al 2011), in spite of a global decrease in polyadenylation efficiency (Kleiman and Manley 1999;Nazeer et al 2011). It is not known whether similar modulators will be present in yeast.…”

p53 as a Therapeutic Target in T-ALL

“…Finally, inhibition of p53 transcriptional outcome is exemplified by YBX1, which is a component of the repressor complex blocking expression of p53 target genes (Shiota et al, 2008;Kim et al, 2008). Proteins cooperating with p53 function were also found among the set of p53-profile neighbors; for example, HNRNPF promotes p53 mRNA 3'-end formation (Decorsiere et al, 2011); DKC1 facilitates p53 translation; heat shock-induced stabilization of p53 occurs via direct binding to HSP90AA1; the purine biosynthesis enzyme GART is involved in p53-activating posttranslational modifications (Bronder & Moran, 2003); and SSRP1 is a component of the p53 transcriptional complex (Keller & Lu, 2002;Keller et al, 2001). There were also examples of genetic cooperation such as NOLC1 and SMARCC1.…”