High Mobility Group A2 protects cancer cells against telomere dysfunction

Oncotarget
Suchitra NatarajanThomas Klonisch

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 axi...Continue Reading

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Citations

Oct 6, 2018·Molecular Oncology·Sabine Hombach-KlonischThomas Klonisch
Dec 28, 2017·Cancer Biomarkers : Section a of Disease Markers·Xiangjun GuoJiashu Li
May 18, 2018·Oxidative Medicine and Cellular Longevity·Huifeng GuYongchang Wei
Aug 23, 2019·International Journal of Oncology·Shizhen ZhangXiaochen Wang
Oct 30, 2016·Journal of Experimental & Clinical Cancer Research : CR·Qing-Xuan WangXiao-Hua Zhang
Jul 28, 2021·Trends in Genetics : TIG·Argyris Papantonis

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Datasets Mentioned

BETA
UTC8505

Methods Mentioned

BETA
pulldown
co-IP
co-immunoprecipitation
Assay
proximity ligation assay
transfection
immunoprecipitation
PCR
pull down
ChIP

Software Mentioned

Duolink Image
TeloView
Zen
ImageJ
Axio Vision
NIH Image J Tools for Analysis of Nuclear Genome Organization ...
TANGO

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