title: DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, James H Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
authors.forename: Yiyong
authors.initials: Y
authors.lastname: Liu
authors.forename: Antonio
authors.initials: A
authors.lastname: Rusinol
authors.forename: Michael
authors.initials: M
authors.lastname: Sinensky
authors.forename: Youjie
authors.initials: Y
authors.lastname: Wang
authors.forename: Yue
authors.initials: Y
authors.lastname: Zou
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002467:Cell Nucleus / Q000473:pathology; D053903:DNA Breaks, Double-Stranded; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D034904:Lamin Type A; D009687:Nuclear Proteins / Q000378:metabolism*; D011371:Progeria / Q000378:metabolism* / Q000473:pathology; D011498:Protein Precursors / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012868:Skin Abnormalities / Q000378:metabolism* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D034904:Lamin Type A; D009687:Nuclear Proteins; D011498:Protein Precursors; D025521:Tumor Suppressor Proteins; C090764:prelamin A; D051231:Farnesyltranstransferase; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases