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DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Liu, Yiyong Sinensky, Michael Wang, Youjie |
| Copyright Year | 2006 |
| 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. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://jcs.biologists.org/content/joces/119/22/4644.full.pdf |
| Alternate Webpage(s) | https://scholarworks.sjsu.edu/cgi/viewcontent.cgi?article=1017&context=biol_pub&httpsredir=1&referer= |
| Alternate Webpage(s) | https://works.bepress.com/michael_sinensky/77/download/ |
| Alternate Webpage(s) | http://jcs.biologists.org/content/early/2006/10/24/jcs.03263.full.pdf |
| PubMed reference number | 17062639v1 |
| Volume Number | 119 |
| Part | 22 |
| Journal | Journal of cell science |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Actinobacillus pleuropneumoniae serotype:Prid:Pt:XXX:Nom:Aggl Biologic Development Cell Cycle Checkpoints DNA Damage Dermatologic disorders Episodic ataxia type 2 (disorder) Farnesyl Transferase Inhibitor Hematological Disease Hereditary Diseases LMNA gene Lamins Patients Phenotype Progeria RCE1 protein, human Restrictive cardiomyopathy Staphylococcal Protein A Syndrome Telangiectasis protein farnesyltransferase |
| Content Type | Text |
| Resource Type | Article |
