Publication Date: 2015.
Telomere length, shape and function depend on a complex of six core telomere-associated proteins referred to as the telosome or shelterin complex. We here demonstrate that the isoform beta2 of the heregulin family of growth factors (HRGbeta2) is a novel interactor of the telosome/shelterin complex in human telomeres. Analysis of protein-protein interactions using a high-throughput yeast two-hybrid (Y2H) screen identified RAP1, the only telomere protein that is conserved from yeasts to mammals, as a novel interacting partner of HRGbeta2. Deletion analysis of RAP1 revealed that the linker domain, a region previously suggested to recruit negative regulators of telomere length, interacts specifically with HRGbeta2. Co-immunoprecipitation and imaging experiments demonstrated that, in addition to RAP1, HRGβ2 could associate with the RAP1-associated telomeric repeat binding factor 2 (TRF2). Deletion analysis of HRGβ2 confirmed that a putative nuclear localization signal (NLS) was necessary for nuclear HRGbeta2 to exert a negative regulation of telomere length whereas the N-terminus (extracellular) amino acids of HRGbeta2 were sufficient to interact with RAP1/TRF2 and promote telomere shortening. Taken together, our studies identify nuclear HRGbeta2 as one of the previously unknown regulators predicted to be recruited by the RAP1 linker domain to negatively regulate telomere length in human cells. Our current findings reveal that a new, but likely not the last, unexpected visitor has arrived to the "telosome/shelterin town".
Author affiliation: Menendez, Javier A.. Catalan Institute of Oncology; España. Girona Biomedical Research Institute; España
Author affiliation: Benboudjema, Louisa. Evanston Northwestern Healthcare Research Institute; Estados Unidos
Author affiliation: Vellón, Luciano. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina
Author affiliation: Rubio, Miguel A.. Hospital de la Santa Creu i Sant Pau. Institut d’Investigació Biomèdica Sant Pau,; España
Author affiliation: Espinoza, Ingrid. University Of Mississippi; Estados Unidos. Lawrence Berkeley National Laboratory; Estados Unidos
Author affiliation: Campisi, Judith. Lawrence Berkeley National Laboratory; Estados Unidos. Buck Institute for Research on Aging; Estados Unidos
Author affiliation: Lupu, Ruth. Mayo Clinic Cancer Center; Estados Unidos. Mayo Clinic. Department of Laboratory Medicine and Pathology; Estados Unidos
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas