DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A

Yiyong Liu; Antonio Rusinol; Michael Sinensky; Youjie Wang; Yue Zou

doi:10.1242/jcs.03263

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DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A

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DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A

Yiyong Liu, Antonio Rusinol, Michael Sinensky, Youjie Wang and Yue Zou

Journal of cell science, Vol.119(Pt 22), pp.4644-4649

11/15/2006

DOI: https://doi.org/10.1242/jcs.03263

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https://hdl.handle.net/2376/109025

PMID: 17062639

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Abstract

Tumor Suppressor Proteins - metabolism

Humans

Lamin Type A

Cell Cycle Proteins - metabolism

Enzyme Inhibitors - pharmacology

DNA Replication

Nuclear Proteins - metabolism

Ataxia Telangiectasia Mutated Proteins

Progeria - metabolism

Fibroblasts - pathology

DNA Breaks, Double-Stranded

Protein Precursors - metabolism

DNA-Binding Proteins - metabolism

Farnesyltranstransferase - metabolism

Skin Abnormalities - metabolism

Cell Nucleus - pathology

Fibroblasts - drug effects

Progeria - pathology

Farnesyltranstransferase - antagonists & inhibitors

Skin Abnormalities - pathology

Protein-Serine-Threonine Kinases - metabolism

Fibroblasts - metabolism

The genetic diseases Hutchinson-Gilford progeria syndrome (HGPS) and restrictive dermopathy (RD) arise from accumulation of farnesylated prelamin A because of defects in the lamin A maturation pathway. Both of these diseases exhibit symptoms that can be viewed as accelerated aging. The mechanism by which accumulation of farnesylated prelamin A leads to these accelerated aging phenotypes is not understood. Here we present evidence that in HGPS and RD fibroblasts, DNA damage checkpoints are persistently activated because of the compromise in genomic integrity. Inactivation of checkpoint kinases Ataxia-telangiectasia-mutated (ATM) and ATR (ATM- and Rad3-related) in these patient cells can partially overcome their early replication arrest. Treatment of patient cells with a protein farnesyltransferase inhibitor (FTI) did not result in reduction of DNA double-strand breaks and damage checkpoint signaling, although the treatment significantly reversed the aberrant shape of their nuclei. This suggests that DNA damage accumulation and aberrant nuclear morphology are independent phenotypes arising from prelamin A accumulation in these progeroid syndromes. Since DNA damage accumulation is an important contributor to the symptoms of HGPS, our results call into question the possibility of treatment of HGPS with FTIs alone.

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Title: DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A
Creators: Yiyong Liu - Department of Biochemistry and Molecular Biology, James H Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
Antonio Rusinol
Michael Sinensky
Youjie Wang
Yue Zou
Publication Details: Journal of cell science, Vol.119(Pt 22), pp.4644-4649
Academic Unit: Biomedical Sciences, Department of
Publisher: England
Grant note: R01 CA086927 / NCI NIH HHS R01 CA086927-05 / NCI NIH HHS R01 CA086927-04 / NCI NIH HHS R56 CA086927 / NCI NIH HHS CA86927 / NCI NIH HHS
Identifiers: 99900547271201842
Language: English
Resource Type: Journal article