hnRNP A1 associates with telomere ends and stimulates telomerase activity

Abstract

Telomerase is a ribonucleoprotein enzyme complex that reverse-transcribes an integral RNA template to add short DNA repeats to the 39-ends of telomeres. G-quadruplex structure in a DNA substrate can block its extension by telomerase. We have found that hnRNP A1-which was previously implicated in telomere length regulation-binds to both single-stranded and structured human telomeric repeats, and in the latter case, it disrupts their higher-order structure. Using an in vitro telomerase assay, we observed that depletion of hnRNP A/B proteins from 293 human embryonic kidney cell extracts dramatically reduced telomerase activity, which was fully recovered upon addition of purified recombinant hnRNP A1. This finding suggests that hnRNP A1 functions as an auxiliary, if not essential, factor of telomerase holoenzyme. We further show, using chromatin immunoprecipitation, that hnRNP A1 associates with human telomeres in vivo. We propose that hnRNP A1 stimulates telomere elongation through unwinding of a G-quadruplex or G-G hairpin structure formed at each translocation step.

Alternative pre-mRNA splicing regulation in cancer: pathways and programs unhinged

“…In another role that is likely significant in cancer, human A1 has been implicated in lengthening and maintaining telomeres, a function that is conserved in C. elegans and possibly yeast (Lin and Zakian 1994;LaBranche et al 1998;Joeng et al 2004). A1 binds to the single-stranded telomeric DNA repeat sequence TAGGGT (a sequence almost identical to the high-affinity SELEXbinding site identified for A1 using RNA), where it is capable of stimulating telomerase activity (Burd and Dreyfuss 1994;Zhang et al 2006). A similar function has been shown for hnRNP A2 (Kamma et al 2001).…”

TERRA transcripts are bound by a complex array of RNA-binding proteins

“…In particular, hnRNP A1, A2B1, A3, D and E can associate with the single-stranded telomeric repeats, although only hnRNP A1 has been shown to infl uence telomere length 11 -13 (reviewed in Ford et al 14 ). Th e hnRNP A1, D and C1 / C2 are also able to interact with human telomerase 12,15 -18 and hnRNP A1 and D can unwind G-quadruplexes 18,20 . Th e hnRNP interaction with TERRA transcripts and the eff ects on TERRA and telomeres that we described here further support a central role of hnRNPs in telomere biology.…”

“…Th e hnRNP proteins can also aff ect chromatin remodelling and transcription in a DNA-independent manner through protein -protein interactions (for example, hnRNP U binds RNA polymerase II) (reviewed in Carpenter et al 19 ). Th e hnRNP A1 and D have been also implicated in transcription owing to their ability to bind to and unwind G-quadruplexes 18,20 . A role for hnRNP A1 in transcription that does not involve unwinding of G-quadruplexes has been also reported 21 .…”

Novel oligosaccharide has suppressive activity against human leukemia cell proliferation

“…6, 7 and 8). Human hnRNP A1 is a single-stranded nucleic acidbinding protein, which has many functions in various aspects of mRNA maturation and in telomere length regulation [20,21]. On the other hand, Murzin et al have observed a novel folding motif in four different proteins, which bind oligonucleotides or oligosaccharides: in nuclease, anticodon binding domain of asp-tRNA synthetase and B-subunits of heat-labile enterotoxin and verotoxin-1 (in some enzymes and toxins) [22].…”