Restoring SIRT6 Expression in Hutchinson-Gilford Progeria Syndrome Cells Impedes Premature Senescence and Formation of Dysmorphic Nuclei

Pathobiology : Journal of Immunopathology, Molecular and Cellular Biology
Helal EndishaLynne W Elmore

Abstract

Mice overexpressing SIRT6 live longer than wild-type mice while SIRT6 knockout mice exhibit similar degenerative phenotypes as individuals with Hutchinson-Gilford progeria syndrome (HGPS). Thus, we sought to test whether levels of SIRT6 are reduced in cells from individuals with HGPS and whether restored SIRT6 expression may impede premature aging phenotypes. Levels of endogenous SIRT6 and progerin in HGPS and normal fibroblasts were assessed by Western blotting and immunofluorescence. A tetracycline-inducible system was utilized to test whether progerin causes a rapid reduction in SIRT6 protein. SIRT6 was overexpressed in HGPS cells via lentiviral infection with biological endpoints including senescence-associated β-galactosidase (SA-β-gal) positivity, frequency of nuclear atypia, the number of 53BP1-positive DNA damage foci and growth rates. Typical HGPS fibroblasts express lower levels of SIRT6 than fibroblasts from normal and atypical HGPS donors. Experimental induction of progerin did not cause a detectable reduction of SIRT6 protein. However, overexpression of SIRT6 in HGPS cells was associated with a reduced frequency of SA-β-gal positivity, fewer misshapen nuclei, fewer DNA damage foci, and increased growth rates. Typic...Continue Reading

Citations

Dec 15, 2015·Rejuvenation Research·Xiao-Yan ZhaiRen-Ke Li
Apr 5, 2016·Nature Structural & Molecular Biology·Luisa TasselliKatrin F Chua
Oct 6, 2015·Cell Regeneration·Hoi-Hung CheungWai-Yee Chan
Feb 18, 2017·Small·João RibasAli Khademhosseini
Oct 21, 2017·The Journal of Cell Biology·Leonid Serebryannyy, Tom Misteli
Aug 10, 2017·Nature Reviews. Molecular Cell Biology·Nard Kubben, Tom Misteli
Nov 8, 2019·Experimental Dermatology·Liz M Garcia-PetersonNihal Ahmad
Feb 13, 2020·Cells·Ray Kreienkamp, Susana Gonzalo
Apr 16, 2020·Aging Cell·Filipa MartinsSandra Rebelo
Nov 25, 2016·Neurochemical Research·Henryk JęśkoJoanna B Strosznajder

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