Cytogenetic Aspects of Werner Syndrome

Salk, Darrell; Au, Kam; Hoehn, Holger; Martin, George M.

doi:10.1007/978-1-4684-7853-2_27

Cited by 49 publications

(31 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These results were consistent with the following previous observations. Salk et al (1985a) preliminarily reported that among four B-lymphoblastoid cell strains, one normal cell line grew continuously over 180 PDLs, while one cell strain from a WRN brother (normal) and two WRN cell strains died out at 158, 54 and 88 PDLs, respectively. Counter et al (1994) reported that two clonal telomerase-negative cell lines died out at 45 and 95 PDLs, while two telomerasepositive cell lines were immortalized.…”

Section: Discussionmentioning

confidence: 99%

“…If this were the case, enhancement of this process by the WRN gene mutation would be possible, since recombination events seem to be activated in WRN cells as speculated from the increased occurrence of chromosomal aberration in WRN cells, including translocation (Figure 7; ref. Salk et al, 1985a). Guarente (1996) proposed the possibility that the WRN gene mutation indeed stimulates recombination between repetitive DNA sequences, since mutation in sgs1, a gene coding the RecQ-type helicase gene of yeast, is known to increase recombination within the hundreds of copies of ribosomal DNA that are tandemly repeated in the genome (Ganglo et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, the following evidence supports this idea. First, chromosomal aberration, known as variegated translocation mosaicism (VTM), is a pathological phenotype of both ®broblasts and EBV-transformed B-lymphoblastoid cell strains (Salk et al, 1985a). Second, impaired S-phase transit has been reported in EBVtransformed B-lymphoblastoid cell strains from WRN patients (Poot et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Abnormal telomere dynamics of B-lymphoblastoid cell strains from Werner's syndrome patients transformed by Epstein – Barr virus

et al. 1997

View full text Add to dashboard Cite

The characteristics of B-lymphoblastoid cell strains transformed by Epstein ± Barr virus (EBV) from normal individuals and Werner's syndrome (WRN) patients were compared. We continuously passaged cell strains from 28 WRN patients and 20 normal individuals for about 2 years corresponding to over 160 population doubling levels (PDLs). First, the WRN mutation signi®cantly suppressed the immortalization: all the 28 cell strains from WRN patients, as well as 15 out of 20 cell strains from normal individuals, died out before 160 PDLs mostly without developing a signi®cant telomerase activity. The remaining ®ve cell strains from normal individuals became moderately/strongly telomerase-positive and, three of them were apparently immortalized with an in®nitively proliferating activity. Second, the monitoring of the telomere length of both normal and WRN cell strains during the culture period suggests that the WRN gene mutation causes abnormal dynamics of the telomere: (1) a signi®cant proportion of WRN cell strains showed drastic shortening or lengthening of telomere lengths during cell passages compared with normal cell strains, and (2) WRN cell strains terminated their life-span at a wide range of telomere length (between 3.5 and 18.5 Kbp), whereas normal cell strains terminated within a narrow telomere length range (between 5.5 and 9 Kbp). The chromosomal aberration characteristic of WRN cells, including translocation was con®rmed in our experiment. We discussed the correlation between the chromosomal instability, abnormal telomere dynamics and inability of immortalization of the WRN B-lymphobloastoid cell strains.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Abnormal telomere dynamics of B-lymphoblastoid cell strains from Werner's syndrome patients transformed by Epstein – Barr virus

et al. 1997

View full text Add to dashboard Cite

show abstract

“…Werner's syndrome (WS) is a rare autosomal recessive disorder characterized by premature aging (Salk et al, 1985) and early onset of various neoplasms, including different types of carcinomas and sarcomas (Goto et al, 1981;Hrabko et al, 1982;Sato et al, 1988). This disorder arises as a consequence of mutations in a gene coding for a protein that is a member of RecQ family of DNA helicases, WRN.…”

Section: Introductionmentioning

confidence: 99%

“…This disorder arises as a consequence of mutations in a gene coding for a protein that is a member of RecQ family of DNA helicases, WRN. One of the hallmarks of WS patients is the genomic instability as evidenced by the spontaneous chromosome anomalies and large deletions in many genes (Salk et al, 1985;Fukuchi et al, 1989). It has been demonstrated that WRN exhibits DNA unwinding activity (Gray et al, 1997;Suzuki et al, 1997) and exonuclease activity residing in the N-terminal region (Huang et al, 1998).…”

mentioning

confidence: 99%

Werner's Syndrome Protein Is Required for Correct Recovery after Replication Arrest and DNA Damage Induced in S-Phase of Cell Cycle

Pichierri

Franchitto

Mosesso

et al. 2001

MBoC

136

140

View full text Add to dashboard Cite

Werner's syndrome (WS) is a rare autosomal recessive disorder that arises as a consequence of mutations in a gene coding for a protein that is a member of RecQ family of DNA helicases, WRN. The cellular function of WRN is still unclear, but on the basis of the cellular phenotypes of WS and of RecQ yeast mutants, its possible role in controlling recombination and/or in maintenance of genomic integrity during S-phase has been envisaged. With the use of two drugs, camptothecin and hydroxyurea, which produce replication-associated DNA damage and/or inhibit replication fork progression, we find that WS cells have a slower rate of repair associated with DNA damage induced in the S-phase and a reduced induction of RAD51 foci. As a consequence, WS cells undergo apoptotic cell death more than normal cells, even if they arrest and resume DNA synthesis at an apparently normal rate. Furthermore, we report that WS cells show a higher background level of DNA strand breaks and an elevated spontaneous induction of RAD51 foci. Our findings support the hypothesis that WRN could be involved in the correct resolution of recombinational intermediates that arise from replication arrest due to either DNA damage or replication fork collapse. INTRODUCTIONWerner's syndrome (WS) is a rare autosomal recessive disorder characterized by premature aging (Salk et al., 1985) and early onset of various neoplasms, including different types of carcinomas and sarcomas (Goto et al., 1981;Hrabko et al., 1982;Sato et al., 1988). This disorder arises as a consequence of mutations in a gene coding for a protein that is a member of RecQ family of DNA helicases, WRN. One of the hallmarks of WS patients is the genomic instability as evidenced by the spontaneous chromosome anomalies and large deletions in many genes (Salk et al., 1985;Fukuchi et al., 1989). It has been demonstrated that WRN exhibits DNA unwinding activity (Gray et al., 1997;Suzuki et al., 1997) and exonuclease activity residing in the N-terminal region (Huang et al., 1998). The cellular function of WRN is still unclear. It has been proposed that helicases are required for various DNA metabolic activities, including progression of replication fork, segregation of newly replicated chromosomes, disruption of the nucleosome structure, DNA supercoiling, transcription, recombination, and repair (Duguet, 1997). In addition, it has been suggested that RecQ family of DNA helicases has an important role in the maintenance of genomic integrity during DNA replication . Studies from yeast show that DNA replication does not proceed normally in absence of RecQ helicase function (Stewart et al., 1997) and in Xenopus laevis the ortholog of WRN is absolutely required for proper formation of replication foci (Yan et al., 1998). Functional interaction between proteins involved in DNA replication, such as replication protein A (RPA) and DNA polymerase ␦, and WRN also have been reported (Shen et al., 1998;Brosh et al., 1999;Kamath-Loeb et al., 2000). Furthermore, in yeast, the RecQlike proteins seem involved in ...

show abstract

WRN mutations in Werner syndrome

1999

View full text Add to dashboard Cite

Werner syndrome (WS) is one of a group of human genetic diseases that have recently been linked to deficits in cellular helicase function. We review the spectrum of WS‐associated WRN mutations, the organization and potential functions of the WRN protein, and potential mechanistic links between the loss of WRN function and pathogenesis of the WS clinical and cellular phenotypes. Hum Mutat 13:271–279, 1999. © 1999 Wiley‐Liss, Inc.

show abstract

Cytogenetic Aspects of Werner Syndrome

Cited by 49 publications

References 6 publications

Abnormal telomere dynamics of B-lymphoblastoid cell strains from Werner's syndrome patients transformed by Epstein – Barr virus

Abnormal telomere dynamics of B-lymphoblastoid cell strains from Werner's syndrome patients transformed by Epstein – Barr virus

Werner's Syndrome Protein Is Required for Correct Recovery after Replication Arrest and DNA Damage Induced in S-Phase of Cell Cycle

WRN mutations in Werner syndrome

Contact Info

Product

Resources

About