Genomic instability and aging-like phenotype in the absence of mammalian SIRT6.
The Sir2 histone deacetylase functions as a chromatin silencer to regulate recombination, genomic stability, and aging in budding yeast. Seven mammalian Sir2 homologs have been identified (SIRT1-SIRT7), and it has been speculated that some may have similar functions to Sir2. Here, we demonstrate that SIRT6 is a nuclear, chromatin-associated protein that promotes resistance to DNA damage and suppresses genomic instability in mouse cells, in association with a role in base excision repair (BER). SIRT6-deficient mice are small and at 2-3 weeks of age develop abnormalities that include profound lymphopenia, loss of subcutaneous fat, lordokyphosis, and severe metabolic defects, eventually dying at about 4 weeks. We conclude that one function of SIRT6 is to promote normal DNA repair, and that SIRT6 loss leads to abnormalities in mice that overlap with aging-associated degenerative processes.
Mostoslavsky
Raul
R
Howard Hughes Medical Institute, The Children's Hospital, CBR Institute for Biomedical Research, Harvard University Medical School, Boston, MA 02115, USA.
Chua
Katrin F
KF
Lombard
David B
DB
Pang
Wendy W
WW
Fischer
Miriam R
MR
Gellon
Lionel
L
Liu
Pingfang
P
Mostoslavsky
Gustavo
G
Franco
Sonia
S
Murphy
Michael M
MM
Mills
Kevin D
KD
Patel
Parin
P
Hsu
Joyce T
JT
Hong
Andrew L
AL
Ford
Ethan
E
Cheng
Hwei-Ling
HL
Kennedy
Caitlin
C
Nunez
Nomeli
N
Bronson
Roderick
R
Frendewey
David
D
Auerbach
Wojtek
W
Valenzuela
David
D
Karow
Margaret
M
Hottiger
Michael O
MO
Hursting
Stephen
S
Barrett
J Carl
JC
Guarente
Leonard
L
Mulligan
Richard
R
Demple
Bruce
B
Yancopoulos
George D
GD
Alt
Frederick W
FW
D000375:Aging / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D030342:Genetic Diseases, Inborn / Q000235:genetics* / Q000473:pathology; D042822:Genomic Instability; D006801:Humans; D017730:Ki-1 Antigen / Q000378:metabolism; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D011836:Radiation Tolerance; D015398:Signal Transduction; D037761:Sirtuins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*
D002843:Chromatin; D017730:Ki-1 Antigen; C501860:Sirt6 protein, mouse; D037761:Sirtuins