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 ATR (ATM- and Rad3-related) checkpoints, and arresting cell-cycle progression.
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Conference Article|
November 21 2011
DNA-damage accumulation and replicative arrest in Hutchinson–Gilford progeria syndrome
Phillip R. Musich;
Phillip R. Musich
1Department of Biochemistry and Molecular Biology, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614-0581, U.S.A.
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Yue Zou
Yue Zou
1
1Department of Biochemistry and Molecular Biology, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614-0581, U.S.A.
1To whom correspondence should be addressed (email zouy@etsu.edu).
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Publisher: Portland Press Ltd
Received:
August 08 2011
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem Soc Trans (2011) 39 (6): 1764–1769.
Article history
Received:
August 08 2011
Citation
Phillip R. Musich, Yue Zou; DNA-damage accumulation and replicative arrest in Hutchinson–Gilford progeria syndrome. Biochem Soc Trans 1 December 2011; 39 (6): 1764–1769. doi: https://doi.org/10.1042/BST20110687
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