Oncotarget

Research Papers:

HIC1 (hypermethylated in cancer 1) SUMOylation is dispensable for DNA repair but is essential for the apoptotic DNA damage response (DDR) to irreparable DNA double-strand breaks (DSBs)

Sonia Paget, Marion Dubuissez, Vanessa Dehennaut, Joe Nassour, Brennan T. Harmon, Nathalie Spruyt, Ingrid Loison, Corinne Abbadie, Brian R. Rood, Dominique Leprince _

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Oncotarget. 2017; 8:2916-2935. https://doi.org/10.18632/oncotarget.13807

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Abstract

Sonia Paget1, Marion Dubuissez1,4, Vanessa Dehennaut1, Joe Nassour1,5, Brennan T. Harmon2, Nathalie Spruyt1, Ingrid Loison1, Corinne Abbadie1, Brian R. Rood3, Dominique Leprince1

1University Lille, CNRS, Institut Pasteur de Lille, UMR 8161-M3T-Mechanisms of Tumorigenesis and Targeted Therapies, Lille, France

2Genomics Core, Children's National Medical Center, Washington DC, USA

3Center for Cancer and Immunology Research, Children's National Medical Center, Washington DC, USA

4Present Address: Maisonneuve-Rosemont Hospital Research Center, Maisonneuve-Rosemont Hospital, Boulevard l'Assomption Montreal, Canada

5Present Address: The Salk Institute for Biological Studies, Molecular and Cell Biology Department, La Jolla, California, USA

Correspondence to:

Dominique Leprince, email: dominique.leprince@ibl.cnrs.fr

Keywords: DNA damage response, HIC1, ATM, MTA1, SUMOylation

Received: June 14, 2016     Accepted: November 23, 2016     Published: December 07, 2016

ABSTRACT

The tumor suppressor gene HIC1 (Hypermethylated In Cancer 1) encodes a transcriptional repressor mediating the p53-dependent apoptotic response to irreparable DNA double-strand breaks (DSBs) through direct transcriptional repression of SIRT1. HIC1 is also essential for DSB repair as silencing of endogenous HIC1 in BJ-hTERT fibroblasts significantly delays DNA repair in functional Comet assays. HIC1 SUMOylation favours its interaction with MTA1, a component of NuRD complexes. In contrast with irreparable DSBs induced by 16-hours of etoposide treatment, we show that repairable DSBs induced by 1 h etoposide treatment do not increase HIC1 SUMOylation or its interaction with MTA1. Furthermore, HIC1 SUMOylation is dispensable for DNA repair since the non-SUMOylatable E316A mutant is as efficient as wt HIC1 in Comet assays. Upon induction of irreparable DSBs, the ATM-mediated increase of HIC1 SUMOylation is independent of its effector kinase Chk2. Moreover, irreparable DSBs strongly increase both the interaction of HIC1 with MTA1 and MTA3 and their binding to the SIRT1 promoter. To characterize the molecular mechanisms sustained by this increased repression potential, we established global expression profiles of BJ-hTERT fibroblasts transfected with HIC1-siRNA or control siRNA and treated or not with etoposide. We identified 475 genes potentially repressed by HIC1 with cell death and cell cycle as the main cellular functions identified by pathway analysis. Among them, CXCL12, EPHA4, TGFβR3 and TRIB2, also known as MTA1 target-genes, were validated by qRT-PCR analyses. Thus, our data demonstrate that HIC1 SUMOylation is important for the transcriptional response to non-repairable DSBs but dispensable for DNA repair.


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