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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)
#MMPMID27935866
Paget S
; Dubuissez M
; Dehennaut V
; Nassour J
; Harmon BT
; Spruyt N
; Loison I
; Abbadie C
; Rood BR
; Leprince D
Oncotarget
2017[Jan]; 8
(2
): 2916-2935
PMID27935866
show ga
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, TGF?R3 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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