High Mobility Group A2 protects cancer cells against telomere dysfunction

Suchitra Natarajan,James R Davie,Dana Henderson,Landon Wark,Farhana Begum,Jeonga Gim,Sabine Hombach-Klonisch,Thomas Klonisch

doi:10.18632/oncotarget.6938

Suchitra Natarajan, James R Davie + Show 6 more

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https://doi.org/10.18632/oncotarget.6938

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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.

Highlights

The nuclear non-histone DNA-binding protein High Mobility Group AT-hook protein 2 (HMGA2) is expressed in embryonic tissues [1] and embryonic stem (ES) cells [2], absent in most normal adult cells and re-expressed in cancer cells [3,4,5,6,7]
Co-IP of HMGA2 resulted in the specific pulldown of Telomeric repeat binding factor 2 (TRF2) in nuclear protein extracts of C1 and UTC8505 transfectants (Fig. 1E) and reverse co-IP with TRF2 resulted in the detection of HMGA2 (Fig. 1F), demonstrating the interaction of HMGA2 with the key shelterin protein TRF2
We have identified HMGA2 as a new interaction partner of the key shelterin member TRF2 at telomeres of interphase nuclei and demonstrated a novel role of HMGA2 in telomere protection in human cancer cells

Summary

Introduction

The nuclear non-histone DNA-binding protein High Mobility Group AT-hook protein 2 (HMGA2) is expressed in embryonic tissues [1] and embryonic stem (ES) cells [2], absent in most normal adult cells and re-expressed in cancer (stem) cells [3,4,5,6,7]. HMGA2 expression directly correlates with the level of malignancy and metastasis in different cancers [3, 10,11,12]. The expression of this oncofetal stem cell factor is regulated by the Lin28 - Let-7 pathway [13, 14]. In breast www.impactjournals.com/oncotarget tumors, increased Wnt/β-catenin signaling was shown to up-regulate HMGA2, promote EMT transformation, and increase tissue invasion of tumor cells [17]

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