Loss of Werner syndrome protein function promotes aberrant mitotic recombination

Prince, Polly R.; Emond, Mary J.; Monnat, Raymond J.

doi:10.1101/gad.877001

Cited by 147 publications

(134 citation statements)

References 43 publications

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“…Single missense-mutant forms of WRN display the same reduced rate of generation of recombinant daughter cells as previously observed in cells lacking WRN protein (Figs. 2, 3 and 5; [12,13]). The likely substrate for WRN in these resolution events are D-loops or Holliday junction-containing intermediates that are generated during gene conversion or synthesis-dependent strand annealing [13,32,33].…”

Section: Discussionmentioning

confidence: 99%

“…2, 3 and 5). These common substrates are likely to include recombination intermediates or products [12,13].…”

Section: Discussionmentioning

confidence: 99%

“…Werner syndrome and control SV40 fibroblast cell lines used for these analyses were from unrelated individuals and have been previously described [12,13]. Both WS cell lines contain WRN mutations and do not make detectable WRN protein.…”

Section: Cell Lines and Cell Culturementioning

confidence: 99%

“…We recently identified a role for the human WRN protein in cell survival and homologous recombination after DNA damage [12,13]. In order to determine whether one or both of the WRN catalytic activities were required for in vivo function, we quantified cell survival and recombination after DNA damage using cells that expressed wildtype WRN or missense-mutant forms of WRN that lacked exonuclease, helicase or both enzymatic activities (E84A, K577M, and E84A/K577M WRN, respectively; Fig.…”

Section: Introductionmentioning

confidence: 99%

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The Werner syndrome protein has separable recombination and survival functions☆

et al. 2004

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The Werner syndrome (WS) protein WRN is unique in possessing a 3 to 5 exonuclease activity in addition to the 3 to 5 helicase activity characteristic of other RecQ proteins. In order to determine in vivo functions of the WRN catalytic activities and their roles in Werner syndrome pathogenesis, we quantified cell survival and homologous recombination after DNA damage in cells expressing WRN missense-mutant proteins that lacked exonuclease and/or helicase activity. Both WRN biochemical activities were required to generate viable recombinant daughter cells. In contrast, either activity was sufficient to promote cell survival after DNA damage in the absence of recombination. These results indicate that WRN has recombination and survival functions that can be separated by missense mutations. Two implications are that Werner syndrome most likely results from the loss of both activities and their associated functions from patient cells, and that WRN missense mutations or polymorphisms could promote genetic instability and cancer in the general population by selectively interfering with recombination in somatic cells.

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Section: Discussionmentioning

confidence: 99%

“…2, 3 and 5). These common substrates are likely to include recombination intermediates or products [12,13].…”

Section: Discussionmentioning

confidence: 99%

Section: Cell Lines and Cell Culturementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Werner syndrome protein has separable recombination and survival functions☆

et al. 2004

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“…TRF2 also interacts with the DNA damage sensing protein ATM, and is thought to inhibit ATM activity specifically at telomeres [81], and WRN [82], the protein that is defective in the human premature aging and cancer-prone disorder Werner syndrome [83,84]. WRN encodes a DNA helicase and exonuclease [85,86] that appears to participate in both the NHEJ and HR DNA repair pathways [87][88][89][90][91][92][93][94]. It is not known whether all TRF1 complexes contain TANK1/2 and/or Ku, or whether all TRF2 complexes contain ATM, WRN, the RMN complex and/or other DNA damage sensors or repair proteins (Fig.…”

Section: Telomere-associated Proteins With Non-telomeric Functionsmentioning

confidence: 99%

Cancer and aging: the importance of telomeres in genome maintenance

Rodier

Kim

Nijjar

et al. 2005

The International Journal of Biochemistry & Cell Biology

120

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Telomeres are the specialized DNA-protein structures that cap the ends of linear chromosomes, thereby protecting them from degradation and fusion by cellular DNA repair processes. In vertebrate cells, telomeres consist of several kilobase pairs of DNA having the sequence TTAGGG, a few hundred base pairs of single-stranded DNA at the 3' end of the telomeric DNA tract, and a host of proteins that organize the telomeric double and single stranded DNA into a protective structure.

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Telomere‐associated proteins: cross‐talk between telomere maintenance and telomere‐lengthening mechanisms

Boeck

Forsyth

Praet

et al. 2009

The Journal of Pathology

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Telomeres, the ends of eukaryotic chromosomes, have been the subject of intense investigation over the last decade. As telomere dysfunction has been associated with ageing and developing cancer, understanding the exact mechanisms regulating telomere structure and function is essential for the prevention and treatment of human cancers and age-related diseases. The mechanisms by which cells maintain telomere lengthening involve either telomerase or the alternative lengthening of the telomere pathway, although specific mechanisms of the latter and the relationship between the two are as yet unknown. Many cellular factors directly (TRF1/TRF2) and indirectly (shelterin-complex, PinX, Apollo and tankyrase) interact with telomeres, and their interplay influences telomere structure and function. One challenge comes from the observation that many DNA damage response proteins are stably associated with telomeres and contribute to several other aspects of telomere function. This review focuses on the different components involved in telomere maintenance and their role in telomere length homeostasis. Special attention is paid to understanding how these telomere-associated factors, and mainly those involved in double-strand break repair, perform their activities at the telomere ends.

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Loss of Werner syndrome protein function promotes aberrant mitotic recombination

Cited by 147 publications

References 43 publications

The Werner syndrome protein has separable recombination and survival functions☆

The Werner syndrome protein has separable recombination and survival functions☆

Cancer and aging: the importance of telomeres in genome maintenance

Telomere‐associated proteins: cross‐talk between telomere maintenance and telomere‐lengthening mechanisms

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