Werner syndrome protein participates in a complex with RAD51, RAD54, RAD54B and ATR in response to ICL-induced replication arrest

Otterlei, Marit; Bruheim, Per; Ahn, Byungchan; Bussen, Wendy; Karmakar, Parimal; Baynton, Kathy; Bohr, Vilhelm A.

doi:10.1242/jcs.03359

Cited by 24 publications

(34 citation statements)

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“…This interaction was enhanced in CPT-treated cells (supplementary material Fig. S8A,B), similarly to a previous report showing that WRN-ATR interaction increases in response to interstrand DNA crosslinks (Otterlei et al, 2006). Also, co-immunofluorescence experiments demonstrated an increase in colocalization between WRN and ATR foci in response to CPT (supplementary material Fig.…”

Section: Wrn Acts As An Upstream Sensor To Cpt-induced Dna Lesionssupporting

confidence: 89%

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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Section: Wrn Acts As An Upstream Sensor To Cpt-induced Dna Lesionssupporting

confidence: 89%

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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“…S6A). To address the specificity of the reaction, we substituted RECQL5 with another human RecQ helicase, WRN, which was previously reported to directly interact with Rad51 (Otterlei et al 2006). WRN, even at 45 nM, did not affect the D-loop reaction catalyzed by either Rad51 K133R (Fig.…”

Section: Human Recql5 Physically Interacts With Rad51 and Suppresses mentioning

confidence: 99%

RECQL5/Recql5 helicase regulates homologous recombination and suppresses tumor formation via disruption of Rad51 presynaptic filaments

Hu¹,

Raynard²,

Sehorn³

et al. 2007

Genes Dev.

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286

411

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Members of the RecQ helicase family play critical roles in genome maintenance. There are five RecQ homologs in mammals, and defects in three of these (BLM, WRN, and RECQL4) give rise to cancer predisposition syndromes in humans. RECQL and RECQL5 have not been associated with a human disease. Here we show that deletion of Recql5 in mice results in cancer susceptibility. Recql5-deficient cells exhibit elevated frequencies of spontaneous DNA double-strand breaks and homologous recombination (HR) as scored using a reporter that harbors a direct repeat, and are prone to gross chromosomal rearrangements in response to replication stress. To understand how RECQL5 regulates HR, we use purified proteins to demonstrate that human RECQL5 binds the Rad51 recombinase and inhibits Rad51-mediated D-loop formation. By biochemical means and electron microscopy, we show that RECQL5 displaces Rad51 from single-stranded DNA (ssDNA) in a reaction that requires ATP hydrolysis and RPA. Together, our results identify RECQL5 as an important tumor suppressor that may act by preventing inappropriate HR events via Rad51 presynaptic filament disruption.[Keywords: Recql5 helicase; DNA repair; homologous recombination; tumor suppressor; Rad51 recombinase] Supplemental material is available at http://www.genesdev.org.

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“…An inactivating mutation in WRN, a homolog of the E. coli RECQ gene, causes WS (Yu et al, 1996). WRN is both a 3′→5′ DNA helicase and a 3′→5′ DNA exonuclease (Huang et al, 1998) and is likely important for several DNA metabolic pathways including replication and repair including homologous recombination (Otterlei et al, 2006). Cells deficient in WRN exhibit genetic instability that includes large chromosomal deletions suggesting a defect in DSB repair.…”

Section: Dna Damage Defective Mammalian Models Of Agingmentioning

confidence: 99%

DNA double-strand breaks: A potential causative factor for mammalian aging?

Han

Mitchell

Hasty

2008

Mechanisms of Ageing and Development

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Aging is a pleiotropic and stochastic process influenced by both genetics and environment. As a result the fundamental underlying causes of aging are controversial and likely diverse. Genome maintenance and in particular the repair of DNA damage is critical to ensure longevity needed for reproduction and as a consequence imperfections or defects in maintaining the genome may contribute to aging. There are many forms of DNA damage with double-strand breaks (DSBs) being the most toxic. Here we discuss DNA DSBs as a potential causative factor for aging including factors that generate DNA DSBs, pathways that repair DNA DSBs, consequences of faulty or failed DSB repair and how these consequences may lead to age-dependent decline in fitness. At the end we compare mouse models of premature aging that are defective for repairing either DSBs or UV lightinduced lesions. Based on these comparisons we believe the basic mechanisms responsible for their aging phenotypes are fundamentally different demonstrating the complex and pleiotropic nature of this process.

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Werner syndrome protein participates in a complex with RAD51, RAD54, RAD54B and ATR in response to ICL-induced replication arrest

Abstract: The first e-press version of this article gave the page range as 5114-5123, whereas it should have been 5137-5146. We apologise for this mistake.

Cited by 24 publications

References 0 publications

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

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

RECQL5/Recql5 helicase regulates homologous recombination and suppresses tumor formation via disruption of Rad51 presynaptic filaments

DNA double-strand breaks: A potential causative factor for mammalian aging?

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