Targeting Werner syndrome protein sensitizes U-2 OS osteosarcoma cells to selenium-induced DNA damage response and necrotic death

2012 ◽  
Vol 420 (1) ◽  
pp. 24-28 ◽  
Author(s):  
Wen-Hsing Cheng ◽  
Ryan T.Y. Wu ◽  
Min Wu ◽  
Caroline R.B. Rocourt ◽  
Jose A. Carrillo ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Werner Syndrome ◽  
Osteosarcoma Cells ◽  
Damage Response ◽  
Werner Syndrome Protein ◽  
Syndrome Protein

scholarly journals Werner Protein Protects Nonproliferating Cells from Oxidative DNA Damage

2005 ◽  
Vol 25 (23) ◽  
pp. 10492-10506 ◽  
Author(s):  
Anna M. Szekely ◽  
Franziska Bleichert ◽  
Astrid Nümann ◽  
Stephen Van Komen ◽  
Elisabeth Manasanch ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Oxidative Dna Damage ◽  
Werner Syndrome ◽  
Human Fibroblasts ◽  
Telomere Maintenance ◽  
Telomere Binding Protein ◽  
Damage Response ◽  
Dividing Cells

ABSTRACT Werner syndrome, caused by mutations of the WRN gene, mimics many changes of normal aging. Although roles for WRN protein in DNA replication, recombination, and telomere maintenance have been suggested, the pathology of rapidly dividing cells is not a feature of Werner syndrome. To identify cellular events that are specifically vulnerable to WRN deficiency, we used RNA interference (RNAi) to knockdown WRN or BLM (the RecQ helicase mutated in Bloom syndrome) expression in primary human fibroblasts. Withdrawal of WRN or BLM produced accelerated cellular senescence phenotype and DNA damage response in normal fibroblasts, as evidenced by induction of γH2AX and 53BP1 nuclear foci. After WRN depletion, the induction of these foci was seen most prominently in nondividing cells. Growth in physiological (3%) oxygen or in the presence of an antioxidant prevented the development of the DNA damage foci in WRN-depleted cells, whereas acute oxidative stress led to inefficient repair of the lesions. Furthermore, WRN RNAi-induced DNA damage was suppressed by overexpression of the telomere-binding protein TRF2. These conditions, however, did not prevent the DNA damage response in BLM-ablated cells, suggesting a distinct role for WRN in DNA homeostasis in vivo. Thus, manifestations of Werner syndrome may reflect an impaired ability of slowly dividing cells to limit oxidative DNA damage.

scholarly journals Central Role for the Werner Syndrome Protein/Poly(ADP-Ribose) Polymerase 1 Complex in the Poly(ADP-Ribosyl)ation Pathway after DNA Damage

2003 ◽  
Vol 23 (23) ◽  
pp. 8601-8613 ◽  
Author(s):  
Cayetano von Kobbe ◽  
Jeanine A. Harrigan ◽  
Alfred May ◽  
Patricia L. Opresko ◽  
Lale Dawut ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cellular Response ◽  
Werner Syndrome ◽  
Alkylating Agents ◽  
Control Cell ◽  
Dna Damaging Agents ◽  
Werner Syndrome Protein ◽  
Syndrome Protein ◽  
Parp 1

ABSTRACT A defect in the Werner syndrome protein (WRN) leads to the premature aging disease Werner syndrome (WS). Hallmark features of cells derived from WS patients include genomic instability and hypersensitivity to certain DNA-damaging agents. WRN contains a highly conserved region, the RecQ conserved domain, that plays a central role in protein interactions. We searched for proteins that bound to this region, and the most prominent direct interaction was with poly(ADP-ribose) polymerase 1 (PARP-1), a nuclear enzyme that protects the genome by responding to DNA damage and facilitating DNA repair. In pursuit of a functional interaction between WRN and PARP-1, we found that WS cells are deficient in the poly(ADP-ribosyl)ation pathway after they are treated with the DNA-damaging agents H2O2 and methyl methanesulfonate. After cellular stress, PARP-1 itself becomes activated, but the poly(ADP-ribosyl)ation of other cellular proteins is severely impaired in WS cells. Overexpression of the PARP-1 binding domain of WRN strongly inhibits the poly(ADP-ribosyl)ation activity in H2O2-treated control cell lines. These results indicate that the WRN/PARP-1 complex plays a key role in the cellular response to oxidative stress and alkylating agents, suggesting a role for these proteins in the base excision DNA repair pathway.

ATM phosphorylation of Nijmegen breakage syndrome protein is required in a DNA damage response

Nature ◽  
2000 ◽  
Vol 405 (6785) ◽  
pp. 477-482 ◽  
Author(s):  
Xiaohua Wu ◽  
Velvizhi Ranganathan ◽  
David S. Weisman ◽  
Walter F. Heine ◽  
David N. Ciccone ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Nijmegen Breakage Syndrome ◽  
Damage Response ◽  
Syndrome Protein

scholarly journals The Werner syndrome protein is required for recruitment of chromatin assembly factor 1 following DNA damage

Oncogene ◽  
2006 ◽  
Vol 26 (26) ◽  
pp. 3811-3822 ◽  
Author(s):  
R Jiao ◽  
J A Harrigan ◽  
I Shevelev ◽  
T Dietschy ◽  
N Selak ◽  
...  
Keyword(s):  
Dna Damage ◽  
Werner Syndrome ◽  
Chromatin Assembly ◽  
Chromatin Assembly Factor ◽  
Assembly Factor ◽  
Werner Syndrome Protein ◽  
Syndrome Protein

scholarly journals Werner Syndrome Protein Phosphorylation by Abl Tyrosine Kinase Regulates Its Activity and Distribution

2003 ◽  
Vol 23 (18) ◽  
pp. 6385-6395 ◽  
Author(s):  
Wen-Hsing Cheng ◽  
Cayetano von Kobbe ◽  
Patricia L. Opresko ◽  
Kesha M. Fields ◽  
Jian Ren ◽  
...  
Keyword(s):  
Dna Damage ◽  
Kinase Inhibitor ◽  
Werner Syndrome ◽  
Sti 571 ◽  
Abl Kinase ◽  
Werner Syndrome Protein ◽  
Domain 3 ◽  
Syndrome Protein

ABSTRACT The Werner syndrome protein (WRN) is a caretaker of the human genome, and the Abl kinase is a regulator of the DNA damage response. Aberrant DNA repair has been linked to the development of cancer. Here, we have identified a direct binding between WRN and c-Abl in vitro via the N-terminal and central regions of WRN and the Src homology domain 3 of c-Abl. After bleomycin treatment in culture, WRN and c-Abl are dissociated and followed by an Abl kinase-dependent WRN relocalization to the nucleoplasm. WRN is a substrate of c-Abl in vitro and in vivo. WRN is tyrosine phosphorylated either transiently by treatment of HeLa cells with bleomycin or constitutively in cells from chronic myeloid leukemia (CML) patients, and these phosphorylations are prevented by treatment with the Abl kinase inhibitor STI-571. Tyrosine phosphorylation of WRN results in inhibition of both WRN exonuclease and helicase activities. Furthermore, anti-WRN immunoprecipitates from CML cells treated with STI-571 show increased 3′→5′ exonuclease activity. These findings suggest a novel signaling pathway by which c-Abl mediates WRN nuclear localization and catalytic activities in response to DNA damage.

The Werner syndrome protein contributes to induction of p53 by DNA damage

2000 ◽  
Vol 14 (14) ◽  
pp. 2138-2140 ◽  
Author(s):  
Gil Blander ◽  
Noa Zalle ◽  
Juan Fernando Martinez Leal ◽  
Ruth Lev Bar‐Or ◽  
Chang‐En Yu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Werner Syndrome ◽  
Werner Syndrome Protein ◽  
Syndrome Protein

scholarly journals Werner Syndrome Protein, WRN, Protects Cells from DNA Damage Induced by the Benzene Metabolite Hydroquinone

2008 ◽  
Vol 107 (2) ◽  
pp. 367-375 ◽  
Author(s):  
Xuefeng Ren ◽  
Sophia Lim ◽  
Martyn T. Smith ◽  
Luoping Zhang
Keyword(s):  
Dna Damage ◽  
Werner Syndrome ◽  
Werner Syndrome Protein ◽  
Syndrome Protein

scholarly journals The Werner syndrome protein affects the expression of genes involved in adipogenesis and inflammation in addition to cell cycle and DNA damage responses

Cell Cycle ◽  
2009 ◽  
Vol 8 (13) ◽  
pp. 2080-2092 ◽  
Author(s):  
Ramachander V.N. Turaga ◽  
Eric R. Paquet ◽  
Mari Sild ◽  
Julien Vignard ◽  
Chantal Garand ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Werner Syndrome ◽  
Expression Of Genes ◽  
Dna Damage Responses ◽  
Werner Syndrome Protein ◽  
Syndrome Protein
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