Functional role of the Werner syndrome RecQ helicase in human fibroblasts

Dhillon, Kiranjit K.; Sidorova, Julia M.; Saintigny, Yannick; Poot, Martin; Gollahon, Katherine A.; Rabinovitch, Peter S.; Monnat, Raymond J.

doi:10.1111/j.1474-9726.2006.00260.x

Cited by 61 publications

(81 citation statements)

References 61 publications

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“…35), a DNA topoisomerase I-trapping agent (camptothecin) (20,36) and hydroxyurea (37). Silencing of WRN in cancer cells increases the chemotherapeutic activity of camptothecin (17) and CDDP (7,38). The epigenetic inactivation of WRN leads to repress WRN proteins, and increases chromosomal instability and sensitivity to chemotherapeutic drugs in cultured cells; and enhances the clinical sensitivity to camptothecin in human colorectal tumors (22).…”

Section: Discussionmentioning

confidence: 99%

RECQL1 and WRN Proteins Are Potential Therapeutic Targets in Head and Neck Squamous Cell Carcinoma

Arai

Chano²,

Futami³

et al. 2011

Cancer Research

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RECQL1 and WRN proteins are RecQ DNA helicases that participate in suppression of DNA hyperrecombination and repair. In this study, we report evidence supporting their candidacy as cancer therapeutic targets. In hypopharyngeal carcinomas, which have the worst prognosis among head and neck squamous cell carcinomas (HNSCC) that are rapidly rising in incidence, we found that RECQL1 and WRN proteins are highly expressed and that siRNA-mediated silencing of either gene suppressed carcinoma cell growth in vitro. Similarly, siRNA administration in a murine xenograft model of hypopharyngeal carcinoma markedly inhibited tumor growth. Moreover, combining either siRNA with cis-platinum (II) diammine dichloride significantly augmented the in vivo anticancer effects of this drug that is used commonly in HNSCC treatment. Notably, we observed no recurrence of some tumors following siRNA treatment in this model. Our findings offer a preclinical proof of concept for RECQL1 and WRN proteins as novel therapeutic targets to treat aggressive HNSCC and perhaps other cancers. Cancer Res; 71(13); 4598-607. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 99%

RECQL1 and WRN Proteins Are Potential Therapeutic Targets in Head and Neck Squamous Cell Carcinoma

Arai

Chano²,

Futami³

et al. 2011

Cancer Research

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show abstract

“…By using CPT, HU and PUVA, several reports show that WRN could be involved in the resolution of recombinational intermediates that arise from replication arrest or collapse (Pichierri et al, 2001;Dhillon et al, 2006;Sidorva et al, 2008). We have recently shown that WRN is involved in facilitating an ATM-mediated checkpoint in response to PUVA induced collapsed forks (Cheng et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

WRN helicase regulates the ATR–CHK1-induced S-phase checkpoint pathway in response to topoisomerase-I–DNA covalent complexes

Patro

Frøhlich

Bohr

et al. 2011

Journal of Cell Science

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SummaryCheckpoints are cellular surveillance and signaling pathways that coordinate the response to DNA damage and replicative stress. Consequently, failure of cellular checkpoints increases susceptibility to DNA damage and can lead to profound genome instability. This study examines the role of a human RECQ helicase, WRN, in checkpoint activation in response to DNA damage. Mutations in WRN lead to genomic instability and the premature aging condition Werner syndrome. Here, the role of WRN in a DNA-damage-induced checkpoint was analyzed in U-2 OS (WRN wild type) and isogenic cells stably expressing WRN-targeted shRNA (WRN knockdown). The results of our studies suggest that WRN has a crucial role in inducing an S-phase checkpoint in cells exposed to the topoisomerase I inhibitor campthothecin (CPT), but not in cells exposed to hydroxyurea. Intriguingly, WRN decreases the rate of replication fork elongation, increases the accumulation of ssDNA and stimulates phosphorylation of CHK1, which releases CHK1 from chromatin in CPT-treated cells. Importantly, knockdown of WRN expression abolished or delayed all these processes in response to CPT. Together, our results strongly suggest an essential regulatory role for WRN in controlling the ATR-CHK1-mediated S-phase checkpoint in CPT-treated cells.

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“…For example, Werner syndrome is caused by a mutation in the RecQ-like DNA helicase WRN [28,29]. WRN is believed to play an important role in the resolution of HR intermediates [30,31], and loss of function of WRN is associated with an increased frequency of deleterious recombination events [32][33][34]. In addition, heritable mutations in ATM, a protein that plays a critical role in initiating DSB repair [35], result in ataxia telangiectasia, a disease that is associated with symptoms of premature aging [17].…”

Section: Introductionmentioning

confidence: 99%

Tissue-specific differences in the accumulation of sequence rearrangements with age

et al. 2008

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Mitotic homologous recombination (HR) is a critical pathway for the accurate repair of DNA double strand breaks (DSBs) and broken replication forks. While generally error-free, HR can occur between misaligned sequences, resulting in deleterious sequence rearrangements that can contribute to cancer and aging. To learn more about the extent to which HR occurs in different tissues during the aging process, we used Fluorescent Yellow Direct Repeat (FYDR) mice in which an HR event in a transgene yields a fluorescent phenotype. Here, we show tissue-specific differences in the accumulation of recombinant cells with age. Unlike pancreas, which shows a dramatic 23-fold increase in recombinant cell frequency with age, skin shows no increase in vivo. In vitro studies indicate that juvenile and aged primary fibroblasts are similarly able to undergo HR in response to endogenous and exogenous DNA damage. Therefore, the lack of recombinant cell accumulation in the skin is most likely not due to an inability to undergo de novo HR events. We propose that tissue-specific differences in the accumulation of recombinant cells with age result from differences in the ability of recombinant cells to persist and clonally expand within tissues.

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Functional role of the Werner syndrome RecQ helicase in human fibroblasts

Cited by 61 publications

References 61 publications

RECQL1 and WRN Proteins Are Potential Therapeutic Targets in Head and Neck Squamous Cell Carcinoma

RECQL1 and WRN Proteins Are Potential Therapeutic Targets in Head and Neck Squamous Cell Carcinoma

WRN helicase regulates the ATR–CHK1-induced S-phase checkpoint pathway in response to topoisomerase-I–DNA covalent complexes

Tissue-specific differences in the accumulation of sequence rearrangements with age

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