title: High Mobility Group A2 protects cancer cells against telomere dysfunction.
abstract: The non-histone chromatin binding protein High Mobility Group AT-hook protein 2 (HMGA2) plays important roles in the repair and protection of genomic DNA in embryonic stem cells and cancer cells. Here we show that HMGA2 localizes to mammalian telomeres and enhances telomere stability in cancer cells. We present a novel interaction of HMGA2 with the key shelterin protein TRF2. We found that the linker (L1) region of HMGA2 contributes to this interaction but the ATI-L1-ATII molecular region of HMGA2 is required for strong interaction with TRF2. This interaction was independent of HMGA2 DNA-binding and did not require the TRF2 interacting partner RAP1 but involved the homodimerization and hinge regions of TRF2. HMGA2 retained TRF2 at telomeres and reduced telomere-dysfunction despite induced telomere stress. Silencing of HMGA2 resulted in (i) reduced binding of TRF2 to telomere DNA as observed by ChIP, (ii) increased telomere instability and (iii) the formation of telomere dysfunction-induced foci (TIF). This resulted in increased telomere aggregation, anaphase bridges and micronuclei. HMGA2 prevented ATM-dependent pTRF2T188 phosphorylation and attenuated signaling via the telomere specific ATM-CHK2-CDC25C DNA damage signaling axis. In summary, our data demonstrate a unique and novel role of HMGA2 in telomere protection and promoting telomere stability in cancer cells. This identifies HMGA2 as a new therapeutic target for the destabilization of telomeres in HMGA2+ cancer cells.
authors.affiliation: Department of Human Anatomy and Cell Science, College of Medicine, University of Manitoba, Winnipeg, Canada.
authors.forename: Suchitra
authors.initials: S
authors.lastname: Natarajan
authors.affiliation: Department of Human Anatomy and Cell Science, College of Medicine, University of Manitoba, Winnipeg, Canada.
authors.forename: Farhana
authors.initials: F
authors.lastname: Begum
authors.affiliation: Department of Human Anatomy and Cell Science, College of Medicine, University of Manitoba, Winnipeg, Canada.
authors.forename: Jeonga
authors.initials: J
authors.lastname: Gim
authors.affiliation: Department of Human Anatomy and Cell Science, College of Medicine, University of Manitoba, Winnipeg, Canada.
authors.forename: Landon
authors.initials: L
authors.lastname: Wark
authors.affiliation: Department of Human Anatomy and Cell Science, College of Medicine, University of Manitoba, Winnipeg, Canada.
authors.forename: Dana
authors.initials: D
authors.lastname: Henderson
authors.affiliation: Children's Hospital Research Institute of Manitoba, Winnipeg, Canada.|Department of Biochemistry and Medical Genetics, College of Medicine, University of Manitoba, Winnipeg, Canada.
authors.forename: James R
authors.initials: JR
authors.lastname: Davie
authors.affiliation: Department of Human Anatomy and Cell Science, College of Medicine, University of Manitoba, Winnipeg, Canada.|Department of Obstetrics, Gynecology and Reproductive Medicine, College of Medicine, University of Manitoba, Winnipeg, Canada.
authors.forename: Sabine
authors.initials: S
authors.lastname: Hombach-Klonisch
authors.affiliation: Department of Human Anatomy and Cell Science, College of Medicine, University of Manitoba, Winnipeg, Canada.|Department of Surgery, College of Medicine, University of Manitoba, Winnipeg, Canada.|Department of Medical Microbiology and Infectious Diseases, College of Medicine, University of Manitoba, Winnipeg, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klonisch
mesh_terms: D045744:Cell Line, Tumor; D025743:HMGA2 Protein / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D055550:Protein Stability; D015398:Signal Transduction / Q000502:physiology; D016615:Telomere / Q000378:metabolism / Q000473:pathology*; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism*
chemical_list: D025743:HMGA2 Protein; D035341:Telomeric Repeat Binding Protein 2
keywords: HMGA2; TRF2; genomic stability; shelterin; telomeres