Heregulin, a new interactor of the telosome/shelterin complex in human telomeres

Menendez, Javier A.; Benboudjema, Louisa; Vellon, Luciano; Rubio, Miguel A.; Espinoza, Ingrid; Campisi, Judith; Lupu, Ruth

doi:10.18632/oncotarget.4962

Heregulin, a new interactor of the telosome/shelterin complex in human telomeres

Journal Article · Wed Jul 22 00:00:00 EDT 2015 · Oncotarget

DOI:https://doi.org/10.18632/oncotarget.4962· OSTI ID:1627986

Menendez, Javier A. ^[1]; Benboudjema, Louisa ^[2]; Vellon, Luciano ^[3]; Rubio, Miguel A. ^[4]; Espinoza, Ingrid ^[5]; Campisi, Judith ^[6]; Lupu, Ruth ^[7]

ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism & Cancer Group, Catalan Institute of Oncology (ICO), Girona, Spain; Girona Biomedical Research Institute (IDIBGI), Girona, Spain; DOE/OSTI
Evanston Northwestern Healthcare Research Institute, Evanston, IL, USA
IBYME, CONICET-Laboratorio de Immunohematología, Buenos Aires, Argentina
Laboratory of Hematology Service, Institut d'Investigació Biomèdica Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
Department of Biochemistry, University of Mississippi, Jackson, MS, USA; Cancer Institute, University of Mississippi, Jackson, MS, USA
Lawrence Berkeley National Laboratory, Life Sciences Division, Berkeley, CA, USA; Buck Institute for Research on Aging, Novato, CA, USA
Mayo Clinic, Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Rochester, MN, USA; Mayo Clinic Cancer Center, Rochester, MN, USA

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 β2 of the heregulin family of growth factors (HRGβ2) 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 HRGβ2. Deletion analysis of RAP1 revealed that the linker domain, a region previously suggested to recruit negative regulators of telomere length, interacts specifically with HRGβ2. 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 HRGβ2 to exert a negative regulation of telomere length whereas the N-terminus (extracellular) amino acids of HRGβ2 were sufficient to interact with RAP1/TRF2 and promote telomere shortening. Taken together, our studies identify nuclear HRGβ2 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”.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC03-76SF00098

OSTI ID:: 1627986

Journal Information:: Oncotarget, Journal Name: Oncotarget Journal Issue: 37 Vol. 6; ISSN 1949-2553

Publisher:: Impact JournalsCopyright Statement

Country of Publication:: United States

Language:: English

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