The premature ageing syndrome protein, WRN, is a 3′→5′ exonuclease

Huang, Shurong; Li, Baomin; Gray, Matthew D.; Oshima, Junko; Mian, I. Saira; Campisi, Judith

doi:10.1038/2410

Cited by 421 publications

(354 citation statements)

References 12 publications

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“…1A). The missense mutations used had been previously shown to inactivate the WRN helicase or exonuclease activity [16,17]. A myc epitope tag was added in-frame to the N-terminus of all of the WRN proteins to allow unambiguous detection of transgene-encoded proteins in the presence of native WRN (Fig.…”

Section: Resultsmentioning

confidence: 99%

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: Resultsmentioning

confidence: 99%

The Werner syndrome protein has separable recombination and survival functions☆

et al. 2004

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“…The 3′-5′ exonuclease activity of p53 is active on both single-stranded DNA (ssDNA) and dsDNA and has a preference for removing mismatches from replicating strand DNA, while paired bases inhibit the exonuclease activity (Huang et al 1998). p53 may act by enhancing a further nuclease, AEN (apoptosis enhancing nuclease), to result in the DNA fragmentation seen in p53-dependent apoptosis (Kawase et al 2008).…”

Section: P53mentioning

confidence: 99%

“…Confusingly, p53, itself a nuclease, strongly inhibits the exonuclease activity of WRN (Brosh et al 2001a), highlighting the complex synergistic/antagonistic interplay between cellular nucleases. Since loss of WRN causes the segmental progeroid Werner's syndrome (Huang et al 1998;Yu et al 1996), this provides a direct evidential link between genome instability and ageing.…”

Section: Wrnmentioning

confidence: 99%

The role of DNA exonucleases in protecting genome stability and their impact on ageing

Mason

Cox

2011

AGE

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Exonucleases are key enzymes involved in many aspects of cellular metabolism and maintenance and are essential to genome stability, acting to cleave DNA from free ends. Exonucleases can act as proofreaders during DNA polymerisation in DNA replication, to remove unusual DNA structures that arise from problems with DNA replication fork progression, and they can be directly involved in repairing damaged DNA. Several exonucleases have been recently discovered, with potentially critical roles in genome stability and ageing. Here we discuss how both intrinsic and extrinsic exonuclease activities contribute to the fidelity of DNA polymerases in DNA replication. The action of exonucleases in processing DNA intermediates during normal and aberrant DNA replication is then assessed, as is the importance of exonucleases in repair of double-strand breaks and interstrand crosslinks. Finally we examine how exonucleases are involved in maintenance of mitochondrial genome stability. Throughout the review, we assess how nuclease mutation or loss predisposes to a range of clinical diseases and particularly ageing.

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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

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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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The premature ageing syndrome protein, WRN, is a 3′→5′ exonuclease

Cited by 421 publications

References 12 publications

The Werner syndrome protein has separable recombination and survival functions☆

The Werner syndrome protein has separable recombination and survival functions☆

The role of DNA exonucleases in protecting genome stability and their impact on ageing

Cancer and aging: the importance of telomeres in genome maintenance

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