Journal
BIOCHEMICAL SOCIETY TRANSACTIONS
Volume 39, Issue -, Pages 1764-1769Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BST20110687
Keywords
DNA repair; genome instability; Hutchinson-Gilford progeria syndrome (HGPS); lamin A; premature aging; xeroderma pigmentosum group A (XPA)
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Funding
- National Cancer Institute (NCI) of the National Institutes of Health (NIH) [CA86927]
- National Institute on Aging (NIA) of the NIH [AG031503]
- Progeria Research Foundation
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A common feature of progeria syndromes is a premature aging phenotype and an enhanced accumulation of DNA damage arising from a compromised repair system. HGPS (Hutchinson-Gilford progeria syndrome) is a severe form of progeria in which patients accumulate progerin, a mutant lamin A protein derived from a splicing variant of the lamin A/C gene (LMNA). Progerin causes chromatin perturbations which result in the formation of DSBs (double-strand breaks) and abnormal DDR (DNA-damage response). In the present article, we review recent findings which resolve some mechanistic details of how progerin may disrupt DDR pathways in HGPS cells. We propose that progerin accumulation results in disruption of functions of some replication and repair factors, causing the mislocalization of XPA (xeroderma pigmentosum group A) protein to the replication forks, replication fork stalling and, subsequently, DNA DSBs. The binding of XPA to the stalled forks excludes normal binding by repair proteins, leading to DSB accumulation, which activates ATM (ataxia telangiectasia mutated) and AIR (ATM- and Rad3-related) checkpoints, and arresting cell-cycle progression.
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