The Werner Syndrome Helicase and Exonuclease Cooperate to Resolve Telomeric D Loops in a Manner Regulated by TRF1 and TRF2

Opresko, Patricia L.; Otterlei, Marit; Graakjær, Jesper; Bruheim, Per; Dawut, Lale; Kølvraa, Steen; May, Alfred; Seidman, Michael M.; Bohr, Vilhem A

doi:10.1016/j.molcel.2004.05.023

Cited by 290 publications

(328 citation statements)

References 41 publications

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“…56,58,59 Although how each biochemical activity of WRN contributes to its function is not fully clarified, several studies indicate specific involvement in different metabolic processes. [60][61][62][63][64][65][66][67] Moreover, WS cells have an elevated spontaneous yield of DNA breakage, which is consistent with the observed high rate of chromosomal rearrangements, 56,68 and depends on an alternative pathway, probably involving break-induced replication, to recover stalled replication forks. 69 These findings support the hypothesis that, upon replication fork stalling, WRN acts to limit DSBs and fork collapse or to promote error-free repair of DSBs.…”

Section: Werner Helicase and Common Fragile Site Stabilitysupporting

confidence: 77%

Understanding the molecular basis of common fragile sites instability: Role of the proteins involved in the recovery of stalled replication forks

Franchitto

Pichierri²

2011

Cell Cycle

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Section: Werner Helicase and Common Fragile Site Stabilitysupporting

confidence: 77%

Understanding the molecular basis of common fragile sites instability: Role of the proteins involved in the recovery of stalled replication forks

Franchitto

Pichierri²

2011

Cell Cycle

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“…In the first case, it is known that the WRN protein interacts with several telomere proteins and unwinds a telomeric D-loop structure (35). Furthermore, the loss of WRN function facilitates the activation of the alternative lengthening of telomeres mechanism, which may engender cancer-relevant chromosomal aberrations and tumor formation in mouse models (36).…”

Section: Discussionmentioning

confidence: 99%

Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer

Agrelo

Cheng

Setién

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

240

227

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Werner syndrome (WS) is an inherited disorder characterized by premature onset of aging, genomic instability, and increased cancer incidence. The disease is caused by loss of function mutations of the WRN gene, a RecQ family member with both helicase and exonuclease activities. However, despite its putative tumorsuppressor function, little is known about the contribution of WRN to human sporadic malignancies. Here, we report that WRN function is abrogated in human cancer cells by transcriptional silencing associated with CpG island-promoter hypermethylation. We also show that, at the biochemical and cellular levels, the epigenetic inactivation of WRN leads to the loss of WRN-associated exonuclease activity and increased chromosomal instability and apoptosis induced by topoisomerase inhibitors. The described phenotype is reversed by the use of a DNA-demethylating agent or by the reintroduction of WRN into cancer cells displaying methylationdependent silencing of WRN. Furthermore, the restoration of WRN expression induces tumor-suppressor-like features, such as reduced colony formation density and inhibition of tumor growth in nude mouse xenograft models. Screening a large collection of human primary tumors (n ‫؍‬ 630) from different cell types revealed that WRN CpG island hypermethylation was a common event in epithelial and mesenchymal tumorigenesis. Most importantly, WRN hypermethylation in colorectal tumors was a predictor of good clinical response to the camptothecin analogue irinotecan, a topoisomerase inhibitor commonly used in the clinical setting for the treatment of this tumor type. These findings highlight the importance of WRN epigenetic inactivation in human cancer, leading to enhanced chromosomal instability and hypersensitivity to chemotherapeutic drugs. DNA methylationW erner syndrome (WS) is an autosomal recessive disease characterized by premature aging and a high incidence of malignant neoplasms (1, 2). Mutations in the WS gene (WRN) are found in patients exhibiting the clinical symptoms of WS (3-5). The vast majority of WRN mutations result in loss of function of the WRN protein (6). The WRN protein has been demonstrated to possess helicase and exonuclease activities (7-9), and cultures of WS cells show increased chromosomal instability, with abundant deletions, reciprocal translocations, and inversions (10, 11).WRN belong to the RecQ family of helicases, which are highly conserved from bacteria to human, and whose members are thought to be essential caretakers of the genome (11,12). In addition to WRN, germline mutations of two other RecQ helicases, BLM in Bloom syndrome and RECQL4 in Rothmund-Thomson syndrome, are also associated with an elevated incidence of cancer (12). Because patients with WRN germline mutations develop a broad spectrum of epithelial and mesenchymal tumors, which is one of the main causes of their death before the age of 50, a tumorsuppressor function for WRN has been proposed. This putative role is also supported by a very high rate of loss of heterozygosity at the chrom...

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“…For example, WRN may play an important role at the telomere, including telomeric D-loop resolution (Opresko et al 2004). It is likely that this requires intramolecular cooperation between the intrinsic helicase and the exonuclease activities of WRN such that the helicase unwinds unusual DNA structures (including G4 quadruplexes which mimic telomeric structures) and is followed by exonuclease activity to process the resulting ends.…”

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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The Werner Syndrome Helicase and Exonuclease Cooperate to Resolve Telomeric D Loops in a Manner Regulated by TRF1 and TRF2

Cited by 290 publications

References 41 publications

Understanding the molecular basis of common fragile sites instability: Role of the proteins involved in the recovery of stalled replication forks

Understanding the molecular basis of common fragile sites instability: Role of the proteins involved in the recovery of stalled replication forks

Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer

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

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