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J Biol Chem. 2018 Jul 13;293(28):11242-11250. doi: 10.1074/jbc.AC118.003325. Epub 2018 May 4.

The epigenetic regulator SIRT7 guards against mammalian cellular senescence induced by ribosomal DNA instability.

Author information

1
From the Department of Medicine, Stanford University School of Medicine, Stanford, California 94305.
2
Geriatric Research, Education, and Clinical Center, Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304, and.
3
Department of Biology, Stanford University, Stanford, California 94305.
4
From the Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, kfchua@stanford.edu.

Abstract

In the yeast Saccharomyces cerevisiae, genomic instability in rDNA repeat sequences is an underlying cause of cell aging and is suppressed by the chromatin-silencing factor Sir2. In humans, rDNA instability is observed in cancers and premature aging syndromes, but its underlying mechanisms and functional consequences remain unclear. Here, we uncovered a pivotal role of sirtuin 7 (SIRT7), a mammalian Sir2 homolog, in guarding against rDNA instability and show that this function of SIRT7 protects against senescence in primary human cells. We found that, mechanistically, SIRT7 is required for association of SNF2H (also called SMARCA5, SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily A, member 5), a component of the nucleolar heterochromatin-silencing complex NoRC, with rDNA sequences. Defective rDNA-heterochromatin silencing in SIRT7-deficient cells unleashed rDNA instability, with excision and loss of rDNA gene copies, which in turn induced acute senescence. Mounting evidence indicates that accumulation of senescent cells significantly contributes to tissue dysfunction in aging-related pathologies. Our findings identify rDNA instability as a driver of mammalian cellular senescence and implicate SIRT7-dependent heterochromatin silencing in protecting against this process.

KEYWORDS:

SIRT7; aging; epigenetics; genomic instability; heterochromatin; nucleolus; rDNA; senescence; sirtuin; sirtuin 7

PMID:
29728458
PMCID:
PMC6052228
DOI:
10.1074/jbc.AC118.003325
[Indexed for MEDLINE]
Free PMC Article

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