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dc.contributor.supervisor Klonisch, Thomas (Human Anatomy and Cell Science) en_US
dc.contributor.author Natarajan, Suchitra
dc.date.accessioned 2016-01-15T19:44:31Z
dc.date.available 2016-01-15T19:44:31Z
dc.date.issued 2013 en_US
dc.identifier.citation Natarajan, Suchitra, Sabine Hombach-Klonisch, Peter Dröge, and Thomas Klonisch. "HMGA2 inhibits apoptosis through interaction with ATR-CHK1 signaling complex in human cancer cells." Neoplasia 15, no. 3 (2013): 263-IN13. en_US
dc.identifier.uri http://hdl.handle.net/1993/31092
dc.description.abstract High Mobility Group AT-hook protein 2 (HMGA2) is a non-histone chromatin binding protein expressed in stem cells, cancer cells but not in normal human somatic cells. The presence of HMGA2 in cancer correlates with advanced neoplastic disease and poor prognosis. HMGA2 plays important roles in Base Excision Repair (BER) and at replication forks. HMGA2 is present at mammalian metaphase telomeres and its loss induces chromosomal aberrations. However, the functional role of HMGA2 at telomeres remains elusive. We hypothesized a protective role of HMGA2 that guards telomeres and modulates DNA damage repair signaling pathways. Employing different HMGA2+ human tumor cell models, we investigated the HMGA2-mediated functions that contribute to chemoresistance in glioblastoma (GB). This study presents a novel interaction of HMGA2 with telomeric protein TRF2 (Telomere Repeat-Binding Factor 2). This interaction retains TRF2 at telomeres, thus capping the telomeres and reducing telomere-dysfunction induced foci despite induced telomere stress. Loss of HMGA2 coincides with increased phosphorylation of TRF2, decreased TRF2 retention at telomeres and increased formation of telomeric aggregates, anaphase bridges and micronuclei. These findings provide new evidence for a unique role of HMGA2 at telomeres as a novel contributor of telomeric integrity. We show that upon DNA damage, HMGA2 causes increased and sustained phosphorylation of Ataxia Telangiectasia and Rad3-related kinase (ATR) and checkpoint kinase 1 (CHK1). Prolonged presence of pCHK1Ser296 coincides with prolonged G2/M block and increased tumor cell survival. The relationship between (ATR)-CHK1 DNA damage response pathway and HMGA2 identifies a novel mechanism by which HMGA2 can alter DNA repair function in cancer cells. We identified HMGA2 as a novel factor contributing to temozolomide (TMZ) resistance in GB. HMGA2 knockdown sensitizes the GB cells to TMZ. We propose a specific combination of FDA-approved drugs, TMZ and Dovitinib (DOV), to increase GB cell death. We show that DOV downregulates key BER proteins, attenuates pSTAT3-coordinated Lin28A and HMGA2 expression. Our results suggest that a sequential therapeutic strategy of pretreating GB cells with DOV followed by a sequence of TMZ and DOV diminishes TMZ resistance and enhances the ability of TMZ to induce GB cell death. Overall, we identified HMGA2 as a multifunctional survival factor in human cancer cells and showed that targeting HMGA2 is a valid strategy to combat HMGA2+ cancer cells. en_US
dc.publisher Elsevier en_US
dc.subject HMGA2 en_US
dc.subject Telomere en_US
dc.subject TRF2-RAP1 en_US
dc.subject ATR-CHK1 en_US
dc.subject Glioblastoma en_US
dc.subject Chemoresistance en_US
dc.subject Genomic stability en_US
dc.title Roles of high mobility group AT-hook protein 2 (HMGA2) in human cancers en_US
dc.degree.discipline Human Anatomy and Cell Science en_US
dc.contributor.examiningcommittee Hombach-Klonisch, Sabine (Human Anatomy and Cell Science) Mai, Sabine (Physiology and Pathophysiology) Simard, Louise (Biochemistry and Medical Genetics) Taubert, Helge (University of Nuremburg) en_US
dc.degree.level Doctor of Philosophy (Ph.D.) en_US
dc.description.note February 2016 en_US


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