 |
PDBsum entry 4n4i
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transcription
|
PDB id
|
|
|
|
4n4i
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Zmynd11 links histone h3.3k36me3 to transcription elongation and tumour suppression.
|
|
|
Authors
|
|
H.Wen,
Y.Li,
Y.Xi,
S.Jiang,
S.Stratton,
D.Peng,
K.Tanaka,
Y.Ren,
Z.Xia,
J.Wu,
B.Li,
M.C.Barton,
W.Li,
H.Li,
X.Shi.
|
|
|
Ref.
|
|
Nature, 2014,
508,
263-268.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
Recognition of modified histones by 'reader' proteins plays a critical role in
the regulation of chromatin. H3K36 trimethylation (H3K36me3) is deposited onto
the nucleosomes in the transcribed regions after RNA polymerase II elongation.
In yeast, this mark in turn recruits epigenetic regulators to reset the
chromatin to a relatively repressive state, thus suppressing cryptic
transcription. However, much less is known about the role of H3K36me3 in
transcription regulation in mammals. This is further complicated by the
transcription-coupled incorporation of the histone variant H3.3 in gene bodies.
Here we show that the candidate tumour suppressor ZMYND11 specifically
recognizes H3K36me3 on H3.3 (H3.3K36me3) and regulates RNA polymerase II
elongation. Structural studies show that in addition to the trimethyl-lysine
binding by an aromatic cage within the PWWP domain, the H3.3-dependent
recognition is mediated by the encapsulation of the H3.3-specific 'Ser 31'
residue in a composite pocket formed by the tandem bromo-PWWP domains of
ZMYND11. Chromatin immunoprecipitation followed by sequencing shows a
genome-wide co-localization of ZMYND11 with H3K36me3 and H3.3 in gene bodies,
and its occupancy requires the pre-deposition of H3.3K36me3. Although ZMYND11 is
associated with highly expressed genes, it functions as an unconventional
transcription co-repressor by modulating RNA polymerase II at the elongation
stage. ZMYND11 is critical for the repression of a transcriptional program that
is essential for tumour cell growth; low expression levels of ZMYND11 in breast
cancer patients correlate with worse prognosis. Consistently, overexpression of
ZMYND11 suppresses cancer cell growth in vitro and tumour formation in mice.
Together, this study identifies ZMYND11 as an H3.3-specific reader of H3K36me3
that links the histone-variant-mediated transcription elongation control to
tumour suppression.
|
|
|
|
|
|
|
