A three-state model for the regulation of telomerase by TERRA and hnRNPA1.
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 heterochromatin. 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 ribonucleoprotein A1 (hnRNPA1) has been implicated in telomere length control. In vivo, TERRA is partially associated with hnRNPA1, and hnRNPA1 is also detected at telomeres. We demonstrate that on binding of TERRA, hnRNPA1 can alleviate the TERRA-mediated inhibition of telomerase. However, when in excess over TERRA, hnRNPA1 becomes itself an inhibitor of telomere extension, on binding of the telomeric DNA substrate. Yet, hnRNPA1 has no notable direct effects on the telomerase catalysis. Our in vitro results suggest that TERRA-mediated telomerase inhibition may be prevented by hnRNPA1 in vivo. Telomere extension by telomerase may require balanced levels of TERRA and hnRNPA1 at telomeres. Thus, TERRA and hnRNPA1 can function as a bimolecular regulator to turn telomerase and the telomere on and off.
Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Frontiers in Genetics National Center of Competence in Research, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
Sophie
S
Redon
Ivo
I
Zemp
Joachim
J
Lingner
D002453:Cell Cycle; D002460:Cell Line; D017931:DNA Primers / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D062085:RNA, Long Noncoding / Q000737:chemistry / Q000378:metabolism*; D012091:Repetitive Sequences, Nucleic Acid; D012261:Ribonucleoproteins / Q000737:chemistry; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000378:metabolism*
D017931:DNA Primers; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D062085:RNA, Long Noncoding; D012261:Ribonucleoproteins; C000619656:hnRNPA1 protein, human; D019098:Telomerase