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Mol Cell Biol. 2017 Jun 29;37(14). pii: e00659-16. doi: 10.1128/MCB.00659-16. Print 2017 Jul 15.

Progerin-Induced Replication Stress Facilitates Premature Senescence in Hutchinson-Gilford Progeria Syndrome.

Author information

1
Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada kwheaton@uottawa.ca benchimo@yorku.ca.
2
Department of Biology, York University, Toronto, Ontario, Canada.
3
Donnelly Centre and Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
4
Department of Biology, York University, Toronto, Ontario, Canada kwheaton@uottawa.ca benchimo@yorku.ca.

Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is caused by a mutation in LMNA that produces an aberrant lamin A protein, progerin. The accumulation of progerin in HGPS cells leads to an aberrant nuclear morphology, genetic instability, and p53-dependent premature senescence. How p53 is activated in response to progerin production is unknown. Here we show that young cycling HGPS fibroblasts exhibit chronic DNA damage, primarily in S phase, as well as delayed replication fork progression. We demonstrate that progerin binds to PCNA, altering its distribution away from replicating DNA in HGPS cells, leading to γH2AX formation, ATR activation, and RPA Ser33 phosphorylation. Unlike normal human cells that can be immortalized by enforced expression of telomerase alone, immortalization of HGPS cells requires telomerase expression and p53 repression. In addition, we show that the DNA damage response in HGPS cells does not originate from eroded telomeres. Together, these results establish that progerin interferes with the coordination of essential DNA replication factors, causing replication stress, and is the primary signal for p53 activation leading to premature senescence in HGPS. Furthermore, this damage response is shown to be independent of progerin farnesylation, implying that unprocessed lamin A alone causes replication stress.

KEYWORDS:

HGPS; aging; p53; progerin; senescence; telomere

PMID:
28483909
PMCID:
PMC5492170
DOI:
10.1128/MCB.00659-16
[Indexed for MEDLINE]
Free PMC Article

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