A three-state model for the regulation of telomerase by TERRA and hnRNPAl

摘要

Telomeres, the physical ends of eukaryotic chromosomes, are transcribed into telomeric repeat-containing RNA (TERRA), a large non-coding RNA, which forms an integral part of telomeric hetero-chromatin. In vitro, naked TERRA molecules are efficient inhibitors of human telomerase, base-pairing via their 5-UUAGGG-3' repeats with the template sequence of telomerase RNA, in addition to contacting the telomerase reverse transcriptase protein subunit. In vivo, however, TERRA-mediated inhibition of telomerase can be prevented by unknown mechanisms. Also, heterogeneous nuclear ribo-nucleoprotein A1 (hnRNPAl) has been implicated in telomere length control. In vivo, TERRA is partially associated with hnRNPAl, and hnRNPAl is also detected at telomeres. We demonstrate that on binding of TERRA, hnRNPAl can alleviate the TERRA-mediated inhibition of telomerase. However, when in excess over TERRA, hnRNPAl becomes itself an inhibitor of telomere extension, on binding of the telomeric DNA substrate. Yet, hnRNPAl hasno notable direct effects on the telomerase catalysis. Our in vitro results suggest that TERRA-mediated telomerase inhibition may be prevented by hnRNPAl in vivo. Telomere extension by telomerase may require balanced levels of TERRA and hnRNPAl at telomeres. Thus, TERRA and hnRNPAl can function as a bimolecular regulator to turn telomerase and the telomere on and off.