Werner syndrome

The helicases are enzymes central to life itself. The nature of double-stranded DNA means that before a polymerase can begin to copy the appropriate region of the nucleic acid, the two strands have to be unwound the separation of the two strands is the function of the helicase (Fig. 2). An indication of the significance of this family of enzymes is seen in the so-called Werner syndrome, where the helicase function required in the suppression of inappropriate recombination events is defective and causes genomic instability and cancer (for a review see Cobb and Bjergbaek 2006). 

Exonuclease domain fused to RecQ-type helicase domain in Werner syndrome protein (WRNp) (Moser et al., 1997 Mushegian et al., 1997)... 

Davis, T., Baird, D. M., Haughton, M. F., Jones, C. J., and Kipling, D. (2005). Prevention of accelerated cell aging in Werner syndrome using a p38 mitogen-activated protein kinase inhibitor. J. Gerontol. A Biol. Sci. Med. Sci. 60,1386-1393. 

Pool M, Gollahon KA, Rabinovitch PS. Werner syndrome lymphoblastoid cells are sensitive to camptothecin-induced apoptosis in S-phase. Hum Genet 1999 104 10-14. 

Cells of patients with Bloom syndrome (BS) have many chromosome breaks and a high frequency of sister chromatid exchanges, perhaps in an effort to correct these breaks. The body is small but well-proportioned.kk A somewhat similar disease, the Werner syndrome (WS), is associated with premature aging.11 The Bloom s protein BLM and the WS gene product WRN are both helicases related to E.coli RecQ. Protein BLM colocalizes with replication protein A as discrete foci in the meiotic synaptonemal complex.1 3 Protein WRN also seems to be associated with DNA replication. Defects... 

Lecka-Czernik, B., Moerman, E., Jones, R., and Goldstein, S. Identification of gene sequences overexpressed in senescent and Werner syndrome human fibroblasts. Exp. Gerontology. 31 (1996) 159-174. 

M. Fry and L.A. Leob, Human Werner syndrome DNA helicase unwinds tetrahelical structures of the fragile X syndrome repeat sequence d(CGG)n,... 

The possibility that the human RecQ helicase, WRN, may function to maintain telomeres has drawn considerable attention because premature aging is the hallmark of Werner syndrome. Afiected individuals develop normally until their teens, then rapidly develop characteristics of aging, including graying hair, alopecia, osteoporosis, type II diabetes and cataracts, and premature death, at an average age of 40. This is accompanied by chromosomal instability and cancer. 

A. S. Kamath-Loeb, E. Johansson, P. M. J. Burgers and L. A. Loeb, Functional interaction between the Werner syndrome protein and DNA polymerase 5, Proceedings of the National Academy Sciences USA, 97 (2000), 4603 608. 

Familial papillary carcinoma Familial oxyphil cell carcinoma Werner syndrome Carney complex Familial MTC, MEN2A, MEN2B Precursor follicular cell tumor Follicular adenoma Papillary or follicular carcinoma Hypercalcaemia Thyroiditis... 

XENOBIOTICS WITH REDOX-DEPENDENT TOXICITY IN WERNER SYNDROME AND EANCONI ANEMIA THE OXIDATIVE STRESS LINK... 

Poot, M. et al., Werner syndrome cells are sensitive to DNA cross-linking drugs, FASEB J., 15, 1224,2001. 

BER, base excision repair DNA-PK, DNA-dependent protein kinase DSB, double strand break MNNG, N-methyl-N -nitro-N-nitrosoguanidine MRC, multiprotein DNA replication complex NER, nucleotide excision repair PAR, poly(ADP-ribose) PARP-1, poly(ADP-ribose) pol)mierase-l PCNA, proliferatii cell nuclear ant en p21, p21 pol 5, DNA pol)mierase 5 SSB, single strand break WRN, Werner syndrome protein. 

The surveillance network against DNA damage implies the interaction of PARP-1 with other factors. The interaction of PARP-1 with p53 has been widely described, thus supporrii the existence of cooperarion between these proteins in maintaining genome int fity (see Chapter 6). PARP-1 aas in concert with Werner syndrome protein (WRN), a protein involved in DNA replication and repair, which interacts direedy with PARP-1 and with PCNA. It has been... 

The growing list of proteins interacting with PCNA includes DNA polymerases TJ, 52 53 54 jgjujinal nucleotidyl transferase, the Werner syndrome helicase, AP... 

Adelfak C, Kontou M, Hirsch-Kauffmann M et al. Physical and functional interaction of the Werner syndrome protein with poly-ADP ribosyl transferase. FEBS Lett 2003 554 55-58. 

Lebel M, Lavoie J, Gaudreault I et al. Genetic cooperation between the Werner syndrome protein and poly(ADP-ribose) polymerase-1 in preventing chromatid breaks, complex chromosomal rearrangements, and cancer in mice. Am J Pathol 2003 162 1559-1569. 

Lebel M, Spillare EA, Harris CC et al. The Werner syndrome gene product copurifies with the DNA replication complex and interacts with PCNA and topoisomerase I. J Biol Chem 1999 274 37795-37799. 

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