SIRT1 contributes to telomere maintenance and augments global homologous recombination

2015-01-13

SIRT1 contributes to telomere maintenance and augments global homologous recombination

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Abstract
Yeast Sir2 deacetylase is a component of the silent information regulator (SIR) complex encompassing Sir2/Sir3/Sir4. Sir2 is recruited to telomeres through Rap1, and this complex spreads into subtelomeric DNA via histone deacetylation. However, potential functions at telomeres for SIRT1, the mammalian orthologue of yeast Sir2, are less clear. We studied both loss of function (SIRT1 deficient) and gain of function (SIRT1super) mouse models. Our results indicate that SIRT1 is a positive regulator of telomere length in vivo and attenuates telomere shortening associated with aging, an effect dependent on telomerase activity. Using chromatin immunoprecipitation assays, we find that SIRT1 interacts with telomeric repeats in vivo. In addition, SIRT1 overexpression increases homologous recombination throughout the entire genome, including telomeres, centromeres, and chromosome arms. These findings link SIRT1 to telomere biology and global DNA repair and provide new mechanistic explanations for the known functions of SIRT1 in protection from DNA damage and some age-associated pathologies.

some notes

We studied both loss of function (SIRT1

deficient) and gain of function (SIRT1 super ) mouse models

SIRT1 is a positive regulator of

telomere length in vivo and attenuates telomere shortening associated with aging

SIRT1 overexpression increases homologous

recombination throughout the entire genome

SIRT1 levels influence telomere length in

mouse embryonic fibroblasts (MEFs)

Increased SIRT1 expression attenuates

telomere erosion with age in adult tissues

SIRT1 effects on telomere length are

largely dependent on telomerase activity

Increased SIRT1 expression augments

homologous recombination at telomeres,
centromeres, and chromosome arms

SIRT1

deficiency triggers a DNA damage
response at chromosome ends

SIRT1 prevents telomere fragility
SIRT1-mediated deacetylation of telomeric

and pericentromeric regions

SIRT1 specifically binds to telomeric

repeats in vivo in induced pluripotent stem
(iPS) cells

However, the molecular mechanisms by which SIRT1

impacts on CR, lifespan, and health span are still largely un-
known

In summary, the findings described in this study demon -

strate that increased expression of SIRT1, the closest mam-
malian orthologue of yeast Sir2, improves telomere length
maintenance in vivo and significantly increases recombination
frequencies at telomeres, centromeres, and chromosome arms

cell culture
TRAP assay
immunoblotting
immunofluorescence
Q-FISH
TRF analysis
B1-SINE Cobra analysis for global DNA methylation
ChIP assay
CO-FISH