RecQ helicases: multifunctional genome caretakers

doi:10.1038/NRC2682

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RecQ helicases: multifunctional genome caretakers

Journal Article•DOI•

RecQ helicases: multifunctional genome caretakers

Wai Kit Chu¹, Ian D. Hickson¹•Institutions (1)

John Radcliffe Hospital¹

01 Sep 2009-Nature Reviews Cancer (Nature Publishing Group)-Vol. 9, Iss: 9, pp 644-654

TL;DR: This Review discusses how these proteins might suppress genomic rearrangements, and therefore function as 'caretaker' tumour suppressors.

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Abstract: Around 1% of the open reading frames in the human genome encode predicted DNA and RNA helicases. One highly conserved group of DNA helicases is the RecQ family. Genetic defects in three of the five human RecQ helicases, BLM, WRN and RECQ4, give rise to defined syndromes associated with cancer predisposition, some features of premature ageing and chromosomal instability. In recent years, there has been a tremendous advance in our understanding of the cellular functions of individual RecQ helicases. In this Review, we discuss how these proteins might suppress genomic rearrangements, and therefore function as 'caretaker' tumour suppressors.

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Journal Article•DOI•

The DNA Damage Response: Making It Safe to Play with Knives

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Alberto Ciccia¹, Stephen J. Elledge², Stephen J. Elledge³, Stephen J. Elledge¹•Institutions (3)

Howard Hughes Medical Institute¹, Harvard University², Brigham and Women's Hospital³

22 Oct 2010-Molecular Cell

TL;DR: This review will focus on how the DDR controls DNA repair and the phenotypic consequences of defects in these critical regulatory functions in mammals.

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3,678 citations

Cites background from "RecQ helicases: multifunctional gen..."

...Premature aging features, such as gray hair and cataracts, have also been associated with the Rothmund-Thomson syndrome (RTS), which is caused by mutations of the RecQ helicase RECQL4 (Chu and Hickson, 2009)....
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...Moreover, WRN can promote HR and telomere maintenance (Chu and Hickson, 2009)....
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...It has been proposed that WRN and RECQL4 might participate in the removal of oxidative lesions by BER (Bohr, 2008)....
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...The high level of CIN of BS patient cells due to hyperrecombination can lead to the development of lymphomas, leukemias, and carcinomas (Chu and Hickson, 2009)....
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...Indeed, the high increase in the number of crossover events, which can be visualized as sister chromatid exchanges or SCEs, displayed by BLM defective cells causes genomic instability (Chu and Hickson, 2009)....
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Journal Article•DOI•

SF1 and SF2 helicases: family matters.

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Margaret E. Fairman-Williams¹, Ulf-Peter Guenther¹, Eckhard Jankowsky¹•Institutions (1)

Case Western Reserve University¹

01 Jun 2010-Current Opinion in Structural Biology

TL;DR: A classification based on protein families that are characterized by typical sequence, structural, and mechanistic features is outlined, which complements and extends existing SF1 and SF2 helicase categorizations and highlights major structural and functional themes for these proteins.

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796 citations

Cites background from "RecQ helicases: multifunctional gen..."

...Some of these clusters encompass proteins that have long been viewed as family, such as the DEAD-box and the RecQ-like proteins [26,27]....
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Journal Article•DOI•

Prioritization of cancer therapeutic targets using CRISPR–Cas9 screens

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Fiona M. Behan¹, Francesco Iorio², Francesco Iorio¹, Gabriele Picco¹, Emanuel Gonçalves¹, Charlotte M. Beaver¹, Giorgia Migliardi³, Rita Santos⁴, Yanhua Rao⁴, Francesco Sassi, Marika Pinnelli³, Rizwan Ansari¹, Sarah Harper¹, David A. Jackson¹, Rebecca McRae¹, Rachel Pooley¹, Piers Wilkinson¹, Dieudonne van der Meer¹, David J. Dow⁴, Carolyn Buser-Doepner⁴, Andrea Bertotti³, Livio Trusolino³, Euan A. Stronach⁴, Julio Saez-Rodriguez, Kosuke Yusa¹, Kosuke Yusa⁵, Mathew J. Garnett¹ - Show less +23 more•Institutions (5)

Wellcome Trust Sanger Institute¹, European Bioinformatics Institute², University of Turin³, GlaxoSmithKline⁴, Kyoto University⁵

10 Apr 2019-Nature

TL;DR: In a screen of 324 human cancer cell lines and utilising a systematic target prioritization framework, the Werner syndrome ATP-dependent helicase is shown to be a synthetic lethal target in tumours from multiple cancer types with microsatellite instability, providing a new target for cancer drug development.

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Abstract: Functional genomics approaches can overcome limitations—such as the lack of identification of robust targets and poor clinical efficacy—that hamper cancer drug development. Here we performed genome-scale CRISPR–Cas9 screens in 324 human cancer cell lines from 30 cancer types and developed a data-driven framework to prioritize candidates for cancer therapeutics. We integrated cell fitness effects with genomic biomarkers and target tractability for drug development to systematically prioritize new targets in defined tissues and genotypes. We verified one of our most promising dependencies, the Werner syndrome ATP-dependent helicase, as a synthetic lethal target in tumours from multiple cancer types with microsatellite instability. Our analysis provides a resource of cancer dependencies, generates a framework to prioritize cancer drug targets and suggests specific new targets. The principles described in this study can inform the initial stages of drug development by contributing to a new, diverse and more effective portfolio of cancer drug targets. In a screen of 324 human cancer cell lines and utilising a systematic target prioritization framework, the Werner syndrome ATP-dependent helicase is shown to be a synthetic lethal target in tumours from multiple cancer types with microsatellite instability, providing a new target for cancer drug development.

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793 citations

Cites background from "RecQ helicases: multifunctional gen..."

...WRN is one of the five RecQ family DNA helicases, is the only one with both a helicase and an exonuclease domain, and plays diverse roles in DNA repair, replication, transcription and telomere maintenance(Chu and Hickson 2009)....
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Journal Article•DOI•

A Distinct Replication Fork Protection Pathway Connects Fanconi Anemia Tumor Suppressors to RAD51-BRCA1/2

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Katharina Schlacher¹, Hong Wu², Maria Jasin¹•Institutions (2)

Memorial Sloan Kettering Cancer Center¹, University of California, Los Angeles²

10 Jul 2012-Cancer Cell

TL;DR: A repair-independent requirement for FA genes, including FANCD2, and BRCA1 in protecting stalled replication forks from degradation is shown, implying a unified molecular mechanism for repair- independent functions of FA, RAD51, and PSA1/2 proteins in preventing genomic instability and suppressing tumorigenesis.

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755 citations

Cites background from "RecQ helicases: multifunctional gen..."

...Loss of BLM causes Bloom syndrome, a developmental disorder with high cancer predisposition (Chu and Hickson, 2009), but is phenotypically distinct from FA....
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...BLM helicase interacts with both FA and BRCA networks (Chu and Hickson, 2009; Deans and West, 2009; Moldovan and D’Andrea, 2009)....
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...On the cellular level, BLM, in partnership with TopIIIa, decatenates fully replicated chromosomes (Chu and Hickson, 2009)....
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Journal Article•DOI•

BLM–DNA2–RPA–MRN and EXO1–BLM–RPA–MRN constitute two DNA end resection machineries for human DNA break repair

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Amitabh V. Nimonkar¹, Jochen Genschel², Eri Kinoshita³, Piotr Polaczek⁴, Judith L. Campbell⁴, Claire Wyman³, Paul Modrich², Stephen C. Kowalczykowski - Show less +4 more•Institutions (4)

University of California, Davis¹, Duke University², Erasmus University Rotterdam³, California Institute of Technology⁴

15 Feb 2011-Genes & Development

TL;DR: Two of the core machineries that initiate recombinational DNA repair in human cells are established: Bloom helicase and DNA2 nuclease, and the complex comprising MRE11, RAD50, and NBS1 (MRN).

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Abstract: Repair of dsDNA breaks requires processing to produce 3′-terminated ssDNA. We biochemically reconstituted DNA end resection using purified human proteins: Bloom helicase (BLM); DNA2 helicase/nuclease; Exonuclease 1 (EXO1); the complex comprising MRE11, RAD50, and NBS1 (MRN); and Replication protein A (RPA). Resection occurs via two routes. In one, BLM and DNA2 physically and specifically interact to resect DNA in a process that is ATP-dependent and requires BLM helicase and DNA2 nuclease functions. RPA is essential for both DNA unwinding by BLM and enforcing 5′ → 3′ resection polarity by DNA2. MRN accelerates processing by recruiting BLM to the end. In the other, EXO1 resects the DNA and is stimulated by BLM, MRN, and RPA. BLM increases the affinity of EXO1 for ends, and MRN recruits and enhances the processivity of EXO1. Our results establish two of the core machineries that initiate recombinational DNA repair in human cells.

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640 citations

Cites background from "RecQ helicases: multifunctional gen..."

...The BLM protein, like its orthologs, functions in many steps of DNA break repair (Harmon and Kowalczykowski 1998; Chu and Hickson 2009; Cejka et al. 2010a,b)....
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...Finally, BLM functions with Topoisomerase IIIa (Chu and Hickson 2009); deletion of BLM would result in loss of Topoisomerase IIIa function, and could explain the lethality of BLM disruption and certain blm alleles (Chester et al. 1998; Luo et al. 2000)....
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...Although there are five RecQ homologs (Bloom helicase [BLM], Werner helicase/nuclease [WRN], RECQ1, RECQ4, and RECQ5) (Chu and Hickson 2009), convincing evidence implicates BLM in resection (Gravel et al. 2008; Nimonkar et al. 2008)....
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References

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Open Access

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Journal Article•DOI•

The double-strand-break repair model for recombination

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Jack W. Szostak¹, Terry L. Orr-Weaver¹, Rodney Rothstein², Franklin W. Stahl³•Institutions (3)

Harvard University¹, Rutgers University², University of Oregon³

01 May 1983-Cell

TL;DR: This work proposes a new mechanism for meiotic recombination, in which events are initiated by double-strand breaks that are enlarged to double- Strand gaps, and postmeiotic segregation can result from heteroduplex DNA formed at the boundaries of the gap-repair region.

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2,387 citations

"RecQ helicases: multifunctional gen..." refers background in this paper

...To initiate HR, blunt-ended DSBs have to be digested in a directional manner (5′→3′) to generate 3′ single-stranded tail...
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Journal Article•DOI•

Positional Cloning of the Werner's Syndrome Gene

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Chang En Yu¹, Junko Oshima¹, Ying-Hui Fu, Ellen M. Wijsman¹, Fuki M. Hisama², Reid S. Alisch, Shellie Matthews¹, Jun Nakura³, Tetsuro Miki³, Samir Ouais, George M. Martin¹, John Mulligan, Gerard D. Schellenberg¹ - Show less +9 more•Institutions (3)

University of Washington¹, Yale University², Osaka University³

12 Apr 1996-Science

TL;DR: The identification of a mutated putative helicase as the gene product of the WS gene suggests that defective DNA metabolism is involved in the complex process of aging in WS patients.

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Abstract: Werner9s syndrome (WS) is an inherited disease with clinical symptoms resembling premature aging. Early susceptibility to a number of major age-related diseases is a key feature of this disorder. The gene responsible for WS (known as WRN ) was identified by positional cloning. The predicted protein is 1432 amino acids in length and shows significant similarity to DNA helicases. Four mutations in WS patients were identified. Two of the mutations are splice-junction mutations, with the predicted result being the exclusion of exons from the final messenger RNA. One of these mutations, which results in a frameshift and a predicted truncated protein, was found in the homozygous state in 60 percent of Japanese WS patients examined. The other two mutations are nonsense mutations. The identification of a mutated putative helicase as the gene product of the WS gene suggests that defective DNA metabolism is involved in the complex process of aging in WS patients.

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1,673 citations

"RecQ helicases: multifunctional gen..." refers background in this paper

...3, respectively, give rise to rare disorders associated with cancer predisposition, premature ageing and developmental defect...
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Journal Article•DOI•

The Bloom's syndrome gene product is homologous to RecQ helicases

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Nathan A. Ellis¹, Joanna Groden², Tian Zhang Ye¹, Joel E. Straughen², David J. Lennon¹, Susan Ciocci¹, Maria Proytcheva¹, James German¹ - Show less +4 more•Institutions (2)

University of Cincinnati Academic Health Center¹, New York Blood Center²

17 Nov 1995-Cell

TL;DR: In this article, a candidate for Bloom's syndrome was identified by direct selection of a cDNA derived from a 250 kb segment of the genome to which BLM had been assigned by somatic crossover point mapping.

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1,351 citations

"RecQ helicases: multifunctional gen..." refers background in this paper

...3, respectively, give rise to rare disorders associated with cancer predisposition, premature ageing and developmental defect...
[...]

Journal Article•DOI•

The Bloom's syndrome helicase suppresses crossing over during homologous recombination

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Leonard Wu¹, Ian D. Hickson¹•Institutions (1)

John Radcliffe Hospital¹

18 Dec 2003-Nature

TL;DR: It is shown that mutations in BLM and hTOPO IIIα together effect the resolution of a recombination intermediate containing a double Holliday junction and prevents exchange of flanking sequences, which has wider implications for the understanding of the process of homologous recombination and the mechanisms that exist to prevent tumorigenesis.

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Abstract: Mutations in BLM, which encodes a RecQ helicase, give rise to Bloom's syndrome, a disorder associated with cancer predisposition and genomic instability. A defining feature of Bloom's syndrome is an elevated frequency of sister chromatid exchanges. These arise from crossing over of chromatid arms during homologous recombination, a ubiquitous process that exists to repair DNA double-stranded breaks and damaged replication forks. Whereas crossing over is required in meiosis, in mitotic cells it can be associated with detrimental loss of heterozygosity. BLM forms an evolutionarily conserved complex with human topoisomerase IIIalpha (hTOPO IIIalpha), which can break and rejoin DNA to alter its topology. Inactivation of homologues of either protein leads to hyper-recombination in unicellular organisms. Here, we show that BLM and hTOPO IIIalpha together effect the resolution of a recombination intermediate containing a double Holliday junction. The mechanism, which we term double-junction dissolution, is distinct from classical Holliday junction resolution and prevents exchange of flanking sequences. Loss of such an activity explains many of the cellular phenotypes of Bloom's syndrome. These results have wider implications for our understanding of the process of homologous recombination and the mechanisms that exist to prevent tumorigenesis.

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1,082 citations

Additional excerpts

...Dissolution generates only non-crossover recombinant product...
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Journal Article•DOI•

Sgs1 helicase and two nucleases Dna2 and Exo1 resect DNA double-strand break ends.

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Zhu Zhu¹, Woo Hyun Chung¹, Eun Yong Shim², Sang Eun Lee², Grzegorz Ira¹ - Show less +1 more•Institutions (2)

Baylor College of Medicine¹, University of Texas Health Science Center at San Antonio²

19 Sep 2008-Cell

TL;DR: Monitoring 5'-strand resection at inducible DSB ends in yeast and identified proteins required for two stages of resection shows that the Mre11-Rad50-Xrs2 complex (MRX) initiates 5' degradation, whereas Sgs1 and Dna2 degrade 5' strands exposing long 3' strands.

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1,027 citations