Defective sister-chromatid cohesion, aneuploidy and cancer predisposition in a mouse model of type II Rothmund-Thomson syndrome

Mann, Michael B.; Hodges, Craig A.; Barnes, Ellen; Vogel, Hannes; Hassold, Terry; Luo, Guangbin

doi:10.1093/hmg/ddi075

Cited by 146 publications

(159 citation statements)

References 61 publications

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“…In addition, the Recql4 À/À , Apc Min/ þ mice had a two-fold increase in the multiplicity of macroadenomas locating in the GI tract and large intestine and macroadenomas were also larger in size. 38 Additional analyses of these mice might shed light on cancers developed in human RECQL4 defective patients.…”

Section: Discussionmentioning

confidence: 99%

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The mutation spectrum in RECQL4 diseases

et al. 2008

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Mutations in the RECQL4 gene can lead to three clinical phenotypes with overlapping features. All these syndromes, Rothmund-Thomson (RTS), RAPADILINO and Baller-Gerold (BGS), are characterized by growth retardation and radial defects, but RAPADILINO syndrome lacks the main dermal manifestation, poikiloderma that is a hallmark feature in both RTS and BGS. It has been previously shown that RTS patients with RECQL4 mutations are at increased risk of osteosarcoma, but the precise incidence of cancer in RAPADILINO and BGS has not been determined. Here, we report that RAPADILINO patients identified as carriers of the c.1390 þ 2delT mutation (p.Ala420_Ala463del) are at increased risk to develop lymphoma or osteosarcoma (6 out of 15 patients). We also summarize all the published RECQL4 mutations and their associated cancer cases and provide an update of 14 novel RECQL4 mutations with accompanying clinical data.

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Section: Discussionmentioning

confidence: 99%

“…In the third mouse model, most of the helicase domain was deleted (exons 9 -13); however, 84% of the knockout mice survived until adulthood. 38 These mice displayed skin and skeleton defects as well as palatal defects all of which have been seen in the RECQL4 patients.…”

Section: Introductionmentioning

confidence: 97%

The mutation spectrum in RECQL4 diseases

et al. 2008

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“…The detailed information for individual genetically modified ES cell lines used in this study is described in the Supplemental Material. Primary MEF cultures were derived from 13.5-d-post-coitus (13.5-dpc) embryos of various genotypes, as described (Hu et al 2005;Mann et al 2005), except that a low oxygen condition (3% O 2 , 5% CO 2 , and 92% N 2 ) was used to reduce oxidative damage-induced stress (Parrinello et al 2003). All MEF cells used in experiments were under passage number 4.…”

Section: Establishment and Culture Of Mouse Es Cells And Mefsmentioning

confidence: 99%

“…Conventional cytogenetic protocols were used for analyzing chromosomal abnormalities as described (Hu et al 2005;Mann et al 2005). …”

Section: Chromosome and Mitotic Abnormalitiesmentioning

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.

292

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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“…G418-resistant clones were further screened by Western blot to identify clones with substantially reduced levels of Rad51. Primary MEFs cultures were derived from 13.5 days-post-coitus embryos of various genotypes as described (Hu et al, 2005;Mann et al, 2005). All MEF cells used in experiments were under passage 4.…”

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confidence: 99%

Recql5 Plays an Important Role in DNA Replication and Cell Survival after Camptothecin Treatment

Zhou

et al. 2009

MBoC

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Disruption of replication can lead to loss of genome integrity and increase of cancer susceptibility in mammals. Thus, a replication impediment constitutes a formidable challenge to these organisms. Recent studies indicate that homologous recombination (HR) plays an important role in suppressing genome instability and promoting cell survival after exposure to various replication inhibitors, including a topoisomerase I inhibitor, camptothecin (CPT). Here, we report that the deletion of RecQ helicase Recql5 in mouse ES cells and embryonic fibroblast (MEF) cells resulted in a significant increase in CPT sensitivity and a profound reduction in DNA replication after the treatment with CPT, but not other DNAdamaging agents. This CPT-induced cell death is replication dependent and occurs primarily after the cells had exited the first cell cycle after CPT treatment. Furthermore, we show that Recql5 functions nonredundantly with Rad51, a key factor for HR to protect mouse ES cells from CPT-induced cytotoxicity. These new findings strongly suggest that Recql5 plays an important role in maintaining active DNA replication to prevent the collapse of replication forks and the accumulation of DSBs in order to preserve genome integrity and to prevent cell death after replication stress as a result of topoisomerase I poisoning. INTRODUCTIONMammalian RecQ helicases share a high degree of homology with the RecQ helicase of Escherichia coli (Nakayama, 2002). These helicases have important roles in maintaining the integrity of the genomes and promoting cell survival in response to various types of genotoxic stress (Hickson, 2003). In addition, some of them have also been implicated in DNA replication (Oakley et al., 2002;Cheok et al., 2005). The only RecQ helicase in E. coli, RecQ, plays an important role in the recovery of genomic replication after DNA damage Hanawalt, 1999, 2001). In both budding yeast and fission yeast, there exist also just a single RecQ helicase. In both species, the RecQ helicase is involved in a number of DNA transaction processes, including repair, recombination and chromosome segregation (Hickson, 2003). Interestingly, these enzymes do not appear to be essential for processive DNA synthesis. Rather, they are required to prevent genomic instability by coordinating replication and recombination events at stalled replication forks (Lambert et al., 2007). Unlike unicellular organisms which have a single RecQ helicase, mammals possess a family of helicases encoded by five different genes, i.e., human RECQL, BLM, WRN, RECQL4, and RECQL5 (Hickson, 2003). Each of these five genes encodes one or multiple polypeptides with distinctive C-and/or N-terminal domains, suggesting that they have related but nonoverlapping functions.In particular, mutations in three of the five RecQ homologues, RECQL4, WRN, and BLM give rise to three distinct genomic instability and cancer-prone genetic disorders: Rothmund-Thomson, Werner, and Bloom syndromes, respectively (Ellis et al., 1995;Yu et al., 1996;Kitao et al., 1999). However, th...

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Defective sister-chromatid cohesion, aneuploidy and cancer predisposition in a mouse model of type II Rothmund-Thomson syndrome

Cited by 146 publications

References 61 publications

The mutation spectrum in RECQL4 diseases

The mutation spectrum in RECQL4 diseases

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

Recql5 Plays an Important Role in DNA Replication and Cell Survival after Camptothecin Treatment

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