Nature13March2008Volume452Number7184pp127252_PKM2
Nature 13 March 2008 Volume 452 Number 7184, pp127-252 PKM2
Nature 13 March 2008 Volume 452 Number 7184, pp127-252
New Human Famsbase for Nature 13 March 2008 Volume 452 Number 7184, pp127-252
PKM2
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Hideaki Umeyama, Ph.D., Professor
School of Pharmacy, Kitasato University
5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
phone : +81-3-5791-6330
fax : +81-3-3446-9553
e-mail:umeyamah@pharm.kitasato-u.ac.jp
港区白金５－９－１
北里大学薬学部教授（理化学研究所客員主管研究員）
梅山秀明
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ENSEMBL Homo sapiens (human)
hsap0
43797
-
Metazoa Chordata
ENSEMBL Homo sapiens (human)
137746 -
Metazoa Chordata
H-Invitational Homo sapiens (human)
-
Metazoa Chordata
NCBI Homo sapiens (cDNA)
-
Metazoa Chordata
Kazusa
hsap1
hsap2
28983
huge0
2038
http://apr2007.archive.ensembl.org/Homo_sapiens/index.html
http://www.h-invitational.jp/
http://hinv.ddbj.nig.ac.jp/index-j.html
http://www.ncbi.nlm.nih.gov/genome/guide/human/
http://www.kazusa.or.jp/huge/
Pyruvate kinase M2 is a phosphotyrosine-binding protein p181
A mechanism whereby the M2 isoform of the glycolytic enzyme pyruvate
kinase (PKM2) can be regulated by tyrosine kinase signalling pathways
through an ability to bind tyrosine-phosphorylated proteins is revealed.
Heather R. Christofk et al.
doi:10.1038/nature06667
Abstract | Full Text | PDF
> Abstract
Article
Nature 452, 181-186 (13 March 2008) | doi:10.1038/nature06667; Received 8
November 2007; Accepted 3 January 2008
ピルビン酸キナーゼ M2 はホスホチロシン結合タンパク質である
. (Title in English; ).Heather R. Christofk1, Matthew G. Vander Heiden1,3,
Ning Wu1, John M. Asara2,4 & Lewis C. Cantley1,4
Department of Systems Biology,
Department of Pathology, Harvard Medical School, Boston, Massachusetts
02115, USA
Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA
Division of Signal Transduction, Beth Israel Deaconess Medical Center,
Boston, Massachusetts 02115, USA
Correspondence to: Lewis C. Cantley1,4 Correspondence and requests for
materials should be addressed to L.C.C. (Email: lcantley@hms.harvard.edu).
Top of pageAbstract 増殖因子は、細胞を刺激して余分な栄養を取り込ませ、それが同
化過程に使われるようにする。これがどのような生化学機構によって遂行されるのかは
完全に解明されていないが、反応はシグナル伝達タンパク質のチロシン残基のリン酸化
によって開始される。ホスホチロシン結合タンパク質探索のために新しくプロテオーム
スクリーニングを行い、解糖にかかわる酵素ピルビン酸キナーゼのヒト M2（胎児）型ア
イソフォーム（PKM2）が、チロシンのリン酸化されたペプチドに直接、選択的に結合す
ることを明らかにした。ホスホチロシンをもつペプチドが PKM2 に結合すると、アロステ
リック活性化因子であるフルクトース-1,6-ビスリン酸が解離し、PKM2 の酵素活性が阻
害される。また、細胞が特定の増殖因子によって刺激されると、このホスホチロシンシ
グナル伝達を介した PKM2 の調節によって、グルコース代謝物がエネルギー生産から同化
過程へと方向転換されることもわかった。これらを総合すると、このホスホチロシン結
合型のピルビン酸キナーゼの発現が、がん細胞の急激な増殖に不可欠であることが示唆
される。
Top of page
M2 isoform of the glycolytic enzyme pyruvate kinase (PKM2)
Pyruvate kinase M2
このホスホチロシン結合型のピルビン酸キナーゼの発現が、がん細胞の急激な増殖に不
可欠であることが示唆される。
7:
P14618
Reports
BLink, Conserved Domains, Links
Pyruvate kinase isozymes M1/M2 (Pyruvate kinase muscle isozyme) (Pyruvate
kinase 2/3) (Cytosolic thyroid hormone-binding protein) (CTHBP) (THBP1)
gi|20178296|sp|P14618.4|KPYM_HUMAN[20178296]
LOCUS
P14618
531 aa
linear
PRI 05-
FEB-2008
DEFINITION Pyruvate kinase isozymes M1/M2 (Pyruvate kinase muscle
isozyme)
(Pyruvate kinase 2/3) (Cytosolic thyroid hormone-binding
protein)
(CTHBP) (THBP1).
ACCESSION
VERSION
DBSOURCE
P14618
P14618.4 GI:20178296
swissprot: locus KPYM_HUMAN, accession P14618;
class: standard.
extra accessions:P14786,Q53GK4,Q96E76,Q9BWB5,Q9UPF2
created: Apr 1, 1990.
sequence updated: Jan 23, 2007.
annotation updated: Feb 5, 2008.
COMMENT
On or before Jul 17, 2007 this sequence version replaced
gi:74740492, gi:2117873, gi:478822, gi:48429214, gi:266427.
[FUNCTION] Glycolytic enzyme that catalyzes the transfer of a
phosphoryl group from phosphoenolpyruvate (PEP) to ADP,
generating
ATP.
[CATALYTIC ACTIVITY] ATP + pyruvate = ADP +
phosphoenolpyruvate.
[COFACTOR] Magnesium.
[COFACTOR] Potassium.
[ENZYME REGULATION] Isoform M2 is allosterically activated by
D-fructose 1,6-biphosphate (FBP). Inhibited by oxalate.
[BIOPHYSICOCHEMICAL PROPERTIES] Kinetic parameters: KM=2.7
mM
for
phosphoenolpyruvate; KM=0.17 mM for phosphoenolpyruvate (in
the
presence of 2mM FBP); KM=0.34 mM for ADP; KM=0.24 mM for ADP
(in
the presence of 2mM FBP); Note=At pH=8 and 32 degrees Celsius.
[PATHWAY] Carbohydrate degradation; glycolysis; pyruvate from
D-glyceraldehyde 3-phosphate: step 5/5.
[SUBUNIT] Homotetramer.
[INTERACTION] Q9NQT4:EXOSC5; NbExp=1; IntAct=EBI-353408,
EBI-371876; Q92597:NDRG1; NbExp=1; IntAct=EBI-353408, EBI716486;
P04049:RAF1; NbExp=3; IntAct=EBI-353408, EBI-365996.
[ALTERNATIVE PRODUCTS] Event=Alternative splicing; Named
isoforms=2; Name=M2; IsoId=P14618-1; Sequence=Displayed;
Name=M1;
IsoId=P14618-2, P14786-1; Sequence=VSP_011101.
[PTM] Phosphorylated upon DNA damage, probably by ATM or ATR.
[MISCELLANEOUS] There are 4 isozymes of pyruvate kinase in
mammals:
L, R, M1 and M2. L type is major isozyme in the liver, R is
found
in red cells, M1 is the main form in muscle, heart and brain,
and
M2 is found in early fetal tissues as well as in most cancer
cells.
[SIMILARITY] Belongs to the pyruvate kinase family.
[WEB RESOURCE] Name=Wikipedia; Note=Pyruvate kinase entry;
URL='http://en.wikipedia.org/wiki/Pyruvate_kinase'.
FEATURES
source
Location/Qualifiers
1..531
/organism="Homo sapiens"
/db_xref="taxon:9606"
gene
1..531
/gene="PKM2"
/note="synonyms: PK2, PK3, PKM"
Protein
1..531
/gene="PKM2"
/product="Pyruvate kinase isozymes M1/M2"
/EC_number="2.7.1.40"
>gi|20178296|sp|P14618.4|KPYM_HUMAN Pyruvate kinase isozymes M1/M2
(Pyruvate kinase muscle isozyme) (Pyruvate kinase 2/3) (Cytosolic thyroid
hormone-binding protein) (CTHBP) (THBP1)
MSKPHSEAGTAFIQTQQLHAAMADTFLEHMCRLDIDSPPITARNTGIICTIGPASRSV
ETLKEMIKSGMN
VARLNFSHGTHEYHAETIKNVRTATESFASDPILYRPVAVALDTKGPEIRTGLIKGSGT
AEVELKKGATL
KITLDNAYMEKCDENILWLDYKNICKVVEVGSKIYVDDGLISLQVKQKGADFLVTEV
ENGGSLGSKKGVN
LPGAAVDLPAVSEKDIQDLKFGVEQDVDMVFASFIRKASDVHEVRKVLGEKGKNIKI
ISKIENHEGVRRF
DEILEASDGIMVARGDLGIEIPAEKVFLAQKMMIGRCNRAGKPVICATQMLESMIKK
PRPTRAEGSDVAN
AVLDGADCIMLSGETAKGDYPLEAVRMQHLIAREAEAAIYHLQLFEELRRLAPITSD
PTEATAVGAVEAS
FKCCSGAIIVLTKSGRSAHQVARYRPRAPIIAVTRNPQTARQAHLYRGIFPVLCKDPVQ
EAWAEDVDLRV
NFAMNVGKARGFFKKGDVVIVLTGWRPGSGFTNTMRVVPVP
Score
E
Sequences producing significant alignments:
(bits) Value
SATB1 reprogrammes gene expression to promote breast tumour growth and
metastasis p187
SATB1 has been identified as a major regulator of gene expression in
breast cancer. SATB1 is often overexpressed in breast tumours, correlating
with poor prognosis, and altering the expression of many genes, which
leads to enhanced tumourigenesis and metastasis.
Hye-Jung Han, Jose Russo, Yoshinori Kohwi and Terumi Kohwi-Shigematsu
doi:10.1038/nature06781
Abstract | Full Text | PDF
See also: Editor's summary
Article
Nature 452, 187-193 (13 March 2008) | doi:10.1038/nature06781; Received 11
September 2007; Accepted 22 January 2008
SATB1 は遺伝子発現のリプログラミングを行い、乳がんの増殖と転移を促進する
. (Title in English; ).Hye-Jung Han1, Jose Russo2, Yoshinori Kohwi1,3 &
Terumi Kohwi-Shigematsu1,3
Life Sciences Division, Lawrence Berkeley National Laboratory, University
of California, Berkeley, California 94720, USA
Breast Cancer Research Laboratory, Fox Chase Cancer Center, Philadelphia,
Pennsylvania 19111, USA
These authors contributed equally to this work.
Correspondence to: Yoshinori Kohwi1,3Terumi Kohwi-Shigematsu1,3
Correspondence and requests for materials should be addressed to T.K.-S.
(Email: Terumiks@lbl.gov) or Y.K. (Email: YKohwi@lbl.gov).
Top of pageAbstract 腫瘍の悪性化に伴い遺伝子発現が大きく変化するが、そのメカニ
ズムに関してはほとんどわかっていない。SATB1 は多数の遺伝子を SATB1 のもとに集合
さ
せ、さらにクロマチンリモデリングに関与する酵素を呼び込み、クロマチン構造と遺伝
子発現を制御するゲノムオーガナイザーである。本論文では、SATB1 が悪性乳がん細胞
で発現されていることを示し、SATB1 の発現レベルはリンパ節浸潤の有無にかかわらず
、患者の予後と密接な関連性（ P <0.0001）がある事実が判明した。悪性度の高い培養
がん細胞（MDA-MB-231）において、RNA 干渉を用いて SATB1 をノックダウンさせると
1,000 を超える遺伝子の発現が変化し、乳腺本来の極性をもった組織形態が回復して腫
瘍形成性が失われ、さらに in vivo で腫瘍増殖や転移能が消失した。逆に、悪性度の
低い培養がん細胞（SKBR3）に SATB1 を強制発現させることで悪性度の高い腫瘍の表現
型
と一致した遺伝子発現パターンを示すようになり、 in vivo で、このがん細胞は新た
に転移能を獲得した。SATB1 は標的遺伝子座において特異的なエピジェネティック修飾
を確立し、そして腫瘍抑制遺伝子の発現を抑制する一方で、転移を促進する遺伝子の発
現を増強するという直接的な制御を行っている。SATB1 は乳がん細胞のクロマチン構成
および転写特性をリプログラムすることで、がん細胞の増殖や転移を促進するというこ
とから、これは腫瘍悪性化の新しいメカニズムを提供している。
SATB1
SATB1 は乳がん細胞のクロマチン構成および転写特性をリプログラムすることで、がん
細胞の増殖や転移を促進するということから、これは腫瘍悪性化の新しいメカニズムを
提供している。
The M2 splice isoform of pyruvate kinase is important for cancer
metabolism and tumour growth p230
Many tumour cells express the M2 form of pyruvate kinase rather than the
usual M1 form. PKM2 is now shown to promote tumorigenesis and switch the
cellular metabolism to increased lactate production and reduced oxygen
consumption, recapitulating key aspects of the Warburg effect.
Heather R. Christofk et al.
doi:10.1038/nature06734
First paragraph | Full Text | PDF
See also: Editor's summary
Letter
Nature 452, 230-233 (13 March 2008) | doi:10.1038/nature06734; Received 18
October 2007; Accepted 19 January 2008
The M2 splice isoform of pyruvate kinase is important for cancer
metabolism and tumour growth
Heather R. Christofk1, Matthew G. Vander Heiden1,2, Marian H. Harris3,
Arvind Ramanathan4, Robert E. Gerszten4,5,6, Ru Wei4, Mark D. Fleming3,
Stuart L. Schreiber4,7 & Lewis C. Cantley1,8
Department of Systems Biology, Harvard Medical School, Boston,
Massachusetts 02115, USA
Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA
Department of Pathology, Children's Hospital, Boston, Massachusetts 02115,
USA
Chemical Biology Program, Broad Institute of Harvard and MIT, Cambridge,
Massachusetts 02142, USA
Cardiology Division and Center for Immunology and Inflammatory Diseases,
Massachusetts General Hospital, Boston, Massachusetts 02129, USA
Donald W. Reynolds Cardiovascular Clinical Research Center on
Atherosclerosis, Harvard Medical School, Boston, Massachusetts 02115, USA
Department of Chemistry and Chemical Biology, Harvard University,
Cambridge, Massachusetts 02138, USA
Division of Signal Transduction, Beth Israel Deaconess Medical Center,
Boston, Massachusetts 02115, USA
Correspondence to: Lewis C. Cantley1,8 Correspondence and requests for
materials should be addressed to L.C.C. (Email: lcantley@hms.harvard.edu).
Top of pageMany tumour cells have elevated rates of glucose uptake but
reduced rates of oxidative phosphorylation. This persistence of high
lactate production by tumours in the presence of oxygen, known as aerobic
glycolysis, was first noted by Otto Warburg more than 75 yr ago1. How
tumour cells establish this altered metabolic phenotype and whether it is
essential for tumorigenesis is as yet unknown. Here we show that a single
switch in a splice isoform of the glycolytic enzyme pyruvate kinase is
necessary for the shift in cellular metabolism to aerobic glycolysis and
that this promotes tumorigenesis. Tumour cells have been shown to express
exclusively the embryonic M2 isoform of pyruvate kinase2. Here we use
short hairpin RNA to knockdown pyruvate kinase M2 expression in human
cancer cell lines and replace it with pyruvate kinase M1. Switching
pyruvate kinase expression to the M1 (adult) isoform leads to reversal of
the Warburg effect, as judged by reduced lactate production and increased
oxygen consumption, and this correlates with a reduced ability to form
tumours in nude mouse xenografts. These results demonstrate that M2
expression is necessary for aerobic glycolysis and that this metabolic
phenotype provides a selective growth advantage for tumour cells in vivo.
UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes
p234
The membrane protein UNC93B interacts with intracellular Toll-like
receptors TLR7 and TLR9. This paper shows that UNC93B specifically
controls TLR trafficking from the endoplasmic reticulum to the
endolysosome but is not required for ligand recognition or signal
initiation.
You-Me Kim, Melanie M. Brinkmann, Marie-Eve Paquet & Hidde L. Ploegh
doi:10.1038/nature06726
First paragraph | Full Text | PDF
Letter
Nature 452, 234-238 (13 March 2008) | doi:10.1038/nature06726; Received 5
September 2007; Accepted 3 January 2008; Published online 27 February 2008
UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes
You-Me Kim1, Melanie M. Brinkmann1, Marie-Eve Paquet1 & Hidde L. Ploegh1
Whitehead Institute for Biomedical Research, 9 Cambridge Center,
Cambridge, Massachusetts 02142, USA
Correspondence to: You-Me Kim1Hidde L. Ploegh1 Correspondence and requests
for materials should be addressed to Y.-M.K. (Email: ykim@wi.mit.edu) or
H.L.P. (Email: ploegh@wi.mit.edu).
Top of pageSignalling by means of toll-like receptors (TLRs) is essential
for the development of innate and adaptive immune responses1, 2, 3.
UNC93B1, essential for signalling of TLR3, TLR7 and TLR9 in both humans
and mice, physically interacts with these TLRs in the endoplasmic
reticulum (ER)4, 5, 6. Here we show that the function of the polytopic
membrane protein UNC93B1 is to deliver the nucleotide-sensing receptors
TLR7 and TLR9 from the ER to endolysosomes. In dendritic cells of 3d mice,
which express an UNC93B1 missense mutant (H412R) incapable of TLR binding,
neither TLR7 nor TLR9 exits the ER. Furthermore, the trafficking and
signalling defects of the nucleotide-sensing TLRs in 3d dendritic cells
are corrected by expression of wild-type UNC93B1. However, UNC93B1 is
dispensable for ligand recognition and signal initiation by TLRs. To our
knowledge, UNC93B1 is the first protein to be identified as a molecule
specifically involved in trafficking of nucleotide-sensing TLRs. By
inhibiting the interaction between UNC93B1 and TLRs it should be possible
to achieve specific regulation of the nucleotide-sensing TLRs without
compromising signalling via the cell-surface-disposed TLRs.
Top of page
An allylic ketyl radical intermediate in clostridial amino-acid
fermentation p239
The pathogenic bacterium Clostridium difficile thrives by fermentation of
L-leucine to ammonia, CO2, isovalerate, and isocaproate under anaerobic
conditions. Ketyl radicals have been proposed to mediate a key reaction
catalysed by an iron?sulphur cluster-containing dehydratase, which
requires activation by ATP-dependent electron transfer from a second
iron?sulphur protein. A kinetically competent product-related allylic
ketyl radical bound to the dehydratase using electron paramagnetic
resonance spectroscopy is identified. These results suggest that other 2hydroxyacyl-CoA dehydratases (and the related benzoyl-CoA reductases) may
employ ketyl radical intermediates. The absence of radical generators
makes these enzymes unprecedented in biochemistry.
Jihoe Kim, Daniel J. Darley, Wolfgang Buckel and Antonio J. Pierik
doi:10.1038/nature06637
First paragraph | Full Text | PDF
See also: Editor's summary | News and Views by Jarrett
Abstract
Letter
Nature 452, 239-242 (13 March 2008) | doi:10.1038/nature06637; Received 6
August 2007; Accepted 10 January 2008
An allylic ketyl radical intermediate in clostridial amino-acid
fermentation
Jihoe Kim1, Daniel J. Darley1,2, Wolfgang Buckel1 & Antonio J. Pierik1
Laboratorium fur Mikrobiologie, Fachbereich Biologie, PhilippsUniversitat, D35032 Marburg, Germany
Present address: Department of Pharmacy and Pharmacology, University of
Bath, Claverton Down, Bath BA2 7AY, UK.
Correspondence to: Antonio J. Pierik1 Correspondence and requests for
materials should be addressed to A.J.P. (Email: pierik@staff.unimarburg.de).
Top of pageThe human pathogenic bacterium Clostridium difficile thrives by
the fermentation of l-leucine to ammonia, CO2, 3-methylbutanoate and 4methylpentanoate under anaerobic conditions1. The reductive branch to 4methylpentanoate proceeds by means of the dehydration of (R)-2-hydroxy-4methylpentanoyl-CoA to 4-methylpent-2-enoyl-CoA, which is chemically the
most demanding step. Ketyl radicals have been proposed2 to mediate this
reaction catalysed by an iron?sulphur-cluster-containing dehydratase,
which requires activation by ATP-dependent electron transfer from a second
iron?sulphur protein functionally similar to the iron protein of
nitrogenase. Here we identify a kinetically competent product-related
allylic ketyl radical bound to the enzyme by electron paramagnetic
resonance spectroscopy employing isotope-labelled (R)-2-hydroxy-4methylpentanoyl-CoA species. We also found that the enzyme generated the
stabilized pentadienoyl ketyl radical from the substrate analogue 2hydroxypent-4-enoyl-CoA, supporting the proposed mechanism. Our results
imply that also other 2-hydroxyacyl-CoA dehydratases3 and the related
benzoyl-CoA reductases4?present in anaerobically living bacteria?employ
ketyl radical intermediates. The absence of radical generators such as
coenzyme B12, S-adenosylmethionine or oxygen makes these enzymes
unprecedented in biochemistry.
Top of page
Erratum
Top
The X-ray crystal structure of RNA polymerase from Archaea p248
Akira Hirata, Brianna J. Klein and Katsuhiko S. Murakami
doi:10.1038/nature06844
Full Text | PDF
Erratum
Nature 452, 248 (13 March 2008) | doi:10.1038/nature06844
The X-ray crystal structure of RNA polymerase from Archaea
Akira Hirata, Brianna J. Klein & Katsuhiko S. Murakami
Nature 451, 851?854 (2008)
In the PDF and print versions of this Letter, the Protein Data Bank (PDB
ID) code of the Sulfolobus solfataricus RNA polymerase (RNAP) was wrongly
listed as 2PM2. The correct code is 2PMZ. This is correct in the full-text
HTML version and on the contents page.
Top of page
nature online
SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric
chromatin
Eriko Michishita et al.
doi:10.1038/nature06736
First paragraph | Full Text | PDF
Letter
Nature advance online publication 12 March 2008 | doi:10.1038/nature06736;
Received 3 December 2007; Accepted 23 January 2008; Published online 12
March 2008
SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric
chromatin
Eriko Michishita1,5, Ronald A. McCord1,5, Elisabeth Berber1,5, Mitomu
Kioi2, Hesed Padilla-Nash6, Mara Damian1,5, Peggie Cheung3, Rika
Kusumoto8, Tiara L. A. Kawahara4, J. Carl Barrett7,9, Howard Y. Chang4,
Vilhelm A. Bohr8, Thomas Ried6, Or Gozani3 & Katrin F. Chua1,5
Department of Medicine, Division of Endocrinology, Gerontology and
Metabolism, School of Medicine,
Department of Radiation Oncology, School of Medicine,
Department of Biological Sciences, and,
Program in Epithelial Biology, School of Medicine, Stanford University,
Stanford, California 94305, USA
Geriatric Research, Education and Clinical Center, VA Palo Alto Health
Care System, Palo Alto, California 94304, USA
Genetics Branch, and,
Laboratory of Biosystems and Cancer, Center for Cancer Research, National
Cancer Institute/NIH, Bethesda, Maryland 20892, USA
Laboratory of Molecular Gerontology, National Institute on Aging, NIH,
Baltimore, Maryland 21224, USA
Present address: Novartis Institutes for Biomedical Research, Cambridge,
Massachusetts 02139, USA.
Correspondence to: Katrin F. Chua1,5 Correspondence and requests for
materials should be addressed to K.F.C. (Email: kfchua@stanford.edu).
Top of pageThe Sir2 deacetylase regulates chromatin silencing and lifespan
in Saccharomyces cerevisiae 1, 2. In mice, deficiency for the Sir2 family
member SIRT6 leads to a shortened lifespan and a premature ageing-like
phenotype3. However, the molecular mechanisms of SIRT6 function are
unclear. SIRT6 is a chromatin-associated protein3, but no enzymatic
activity of SIRT6 at chromatin has yet been detected, and the identity of
physiological SIRT6 substrates is unknown. Here we show that the human
SIRT6 protein is an NAD+-dependent, histone H3 lysine 9 (H3K9) deacetylase
that modulates telomeric chromatin. SIRT6 associates specifically with
telomeres, and SIRT6 depletion leads to telomere dysfunction with end-toend chromosomal fusions and premature cellular senescence. Moreover,
SIRT6-depleted cells exhibit abnormal telomere structures that resemble
defects observed in Werner syndrome, a premature ageing disorder4, 5. At
telomeric chromatin, SIRT6 deacetylates H3K9 and is required for the
stable association of WRN, the factor that is mutated in Werner syndrome4,
5. We propose that SIRT6 contributes to the propagation of a specialized
chromatin state at mammalian telomeres, which in turn is required for
proper telomere metabolism and function. Our findings constitute the first
identification of a physiological enzymatic activity of SIRT6, and link
chromatin regulation by SIRT6 to telomere maintenance and a human
premature ageing syndrome.
Top of page