Characterization of the human and mouse WRN 3'-&gt;5' exonuclease

Huang, Shurong; Beresten, S. F.; Li, Baomin; Oshima, Junko; Ellis, Nathan A.; Campisi, Judith

doi:10.1093/nar/28.12.2396

Cited by 151 publications

(158 citation statements)

References 39 publications

(67 reference statements)

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“…It is therefore of particular interest that WRN possesses a-3 ′− 5 ′ exonuclease activity, unique within the RecQ family (Huang et al ., 1998;Kamath Loeb et al ., 1998;Suzuki et al ., 1999). Although WRN alone shows preference for recessed 3 ′ ends (Huang et al ., 2000), it may cleave alternative substrates in the presence of the dsDNA-PK associated Ku protein (Cooper et al ., 2000;Orren et al ., 2001), which may be recruited to collapsed forks by virtue of their dsDNA ends. The structures formed once replication forks collapse may not be completely duplex in nature, and WRN exonuclease has been shown to be stimulated by melted regions of DNA (Machwe et al ., 2002).…”

Section: Discussionmentioning

confidence: 99%

Asymmetry of DNA replication fork progression in Werner's syndrome

et al. 2002

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SummaryHuman aging is associated with accumulation of cells that have undergone replicative senescence. The rare premature aging Werner's syndrome (WS) provides a phenocopy of normal human aging and WS patient cells recapitulate the aging phenotype in culture as they rapidly lose the ability to proliferate or replicate their DNA. WS is associated with loss of functional WRN protein.Although the biochemical properties of WRN protein, which possesses both helicase and exonuclease activities, suggest an involvement in DNA metabolism, its action in cells is not clear. Here, we provide experimental evidence for a role of the WRN protein in DNA replication in normally proliferating cells. Most importantly, we demonstrate that in the absence of functional WRN protein, replication forks from origins of bidirectional replication fail to progress normally, resulting in marked asymmetry of bidirectional forks. We propose that WRN acts in normal DNA replication to prevent collapse of replication forks or to resolve DNA junctions at stalled replication forks, and that loss of this capacity may be a contributory factor in premature aging.

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Section: Discussionmentioning

confidence: 99%

Asymmetry of DNA replication fork progression in Werner's syndrome

et al. 2002

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“…Whereas phosphorylation prevents Fen1-mediated stimulation of PCNA, acetylation by p300 appears to reduce the ability of Fen1 to bind to DNA and to function as a nuclease, with no effect on its PCNA interaction (Table III). WRN also stimulates strand displacement activities of pol ß [88,89] and is included herein as a gap tailoring protein since it removes 3'lesions via its 3'⇒5' exonuclease activity [124] and acts as a participant in promoting long-patch BER. Similar to Fen1, phosphorylation of WRN decreases its catalytic activity (Table III).…”

Section: Post-translational Modifications Of Ber Gap Tailoring Proteinsmentioning

confidence: 99%

A unified view of base excision repair: Lesion-dependent protein complexes regulated by post-translational modification

Almeida¹,

Sobol²

2007

DNA Repair

385

374

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Base excision repair (BER) proteins act upon a significantly broad spectrum of DNA lesions that result from endogenous and exogenous sources. Multiple sub-pathways of BER (short-path or longpatch) and newly designated DNA repair pathways (e.g., SSBR and NIR) that utilize BER proteins complicate any comprehensive understanding of BER and its role in genome maintenance, chemotherapeutic response, neurodegeneration, cancer or aging. Herein, we propose a unified model of BER, comprised of three functional processes: Lesion Recognition/Strand Scission, Gap Tailoring and DNA Synthesis/Ligation, each represented by one or more multiprotein complexes and coordinated via the XRCC1/DNA Ligase III and PARP1 scaffold proteins. BER therefore may be represented by a series of repair complexes that assemble at the site of the DNA lesion and mediates repair in a coordinated fashion involving protein-protein interactions that dictate subsequent steps or sub-pathway choice. Complex formation is influenced by post-translational protein modifications that arise from the cellular state or the DNA damage response, providing an increase in specificity and efficiency to the BER pathway. In this review, we have summarized the reported BER proteinprotein interactions and protein post-translational modifications and discuss the impact on DNA repair capacity and complex formation.

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“…Unlike other RecQ helicases, in addition to helicase activity, WRN has a well-characterised 3′-5′ exonuclease domain (Huang et al 2000) which is highly conserved and of the DnaQ exonuclease family (Perry et al 2006) (Table 2). In Drosophila, and other invertebrate and plant species, the exonuclease appears as an autonomous protein (Boubriak et al 2009;Plchova et al 2003;Saunders et al 2008;Sekelsky et al 1999).…”

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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Characterization of the human and mouse WRN 3'->5' exonuclease

Cited by 151 publications

References 39 publications

Asymmetry of DNA replication fork progression in Werner's syndrome

Asymmetry of DNA replication fork progression in Werner's syndrome

A unified view of base excision repair: Lesion-dependent protein complexes regulated by post-translational modification

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

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