scholarly journals RecQ helicases: suppressors of tumorigenesis and premature aging

2003 ◽  
Vol 374 (3) ◽  
pp. 577-606 ◽  
Author(s):  
Csanád Z. BACHRATI ◽  
Ian D. HICKSON
Keyword(s):  
Replication Fork ◽  
Germ Line ◽  
Genetic Disorders ◽  
Premature Aging ◽  
Recq Helicase ◽  
Dna Helicases ◽  
Recq Helicases ◽  
Protein Partners ◽  
Line Defects ◽  
Rothmund Thomson Syndrome

The RecQ helicases represent a subfamily of DNA helicases that are highly conserved in evolution. Loss of RecQ helicase function leads to a breakdown in the maintenance of genome integrity, in particular hyper-recombination. Germ-line defects in three of the five known human RecQ helicases give rise to defined genetic disorders associated with cancer predisposition and/or premature aging. These are Bloom's syndrome, Werner's syndrome and Rothmund–Thomson syndrome, which are caused by defects in the genes BLM, WRN and RECQ4 respectively. Here we review the properties of RecQ helicases in organisms from bacteria to humans, with an emphasis on the biochemical functions of these enzymes and the range of protein partners that they operate with. We will discuss models in which RecQ helicases are required to protect against replication fork demise, either through prevention of fork breakdown or restoration of productive DNA synthesis.

scholarly journals Mechanisms of RecQ helicases in pathways of DNA metabolism and maintenance of genomic stability

2006 ◽  
Vol 398 (3) ◽  
pp. 319-337 ◽  
Author(s):  
Sudha Sharma ◽  
Kevin M. Doherty ◽  
Robert M. Brosh
Keyword(s):  
Protein Interactions ◽  
Human Disease ◽  
Genome Stability ◽  
Molecular Motor ◽  
Genomic Stability ◽  
Premature Aging ◽  
Dna Metabolism ◽  
Dna Helicases ◽  
Recq Helicases ◽  
Hydrolysis Of

Helicases are molecular motor proteins that couple the hydrolysis of NTP to nucleic acid unwinding. The growing number of DNA helicases implicated in human disease suggests that their vital specialized roles in cellular pathways are important for the maintenance of genome stability. In particular, mutations in genes of the RecQ family of DNA helicases result in chromosomal instability diseases of premature aging and/or cancer predisposition. We will discuss the mechanisms of RecQ helicases in pathways of DNA metabolism. A review of RecQ helicases from bacteria to human reveals their importance in genomic stability by their participation with other proteins to resolve DNA replication and recombination intermediates. In the light of their known catalytic activities and protein interactions, proposed models for RecQ function will be summarized with an emphasis on how this distinct class of enzymes functions in chromosomal stability maintenance and prevention of human disease and cancer.

scholarly journals Molecular characteristics of reiterative DNA unwinding by the Caenorhabditis elegans RecQ helicase

2019 ◽  
Vol 47 (18) ◽  
pp. 9708-9720 ◽  
Author(s):  
Seoyun Choi ◽  
Seung-Won Lee ◽  
Hajin Kim ◽  
Byungchan Ahn
Keyword(s):  
Caenorhabditis Elegans ◽  
Single Molecule ◽  
Molecular Mechanisms ◽  
Protein A ◽  
Direct Interaction ◽  
Premature Aging ◽  
Molecular Characteristics ◽  
Dna Unwinding ◽  
Recq Helicase ◽  
Recq Helicases

Abstract The RecQ family of helicases is highly conserved both structurally and functionally from bacteria to humans. Defects in human RecQ helicases are associated with genetic diseases that are characterized by cancer predisposition and/or premature aging. RecQ proteins exhibit 3′-5′ helicase activity and play critical roles in genome maintenance. Recent advances in single-molecule techniques have revealed the reiterative unwinding behavior of RecQ helicases. However, the molecular mechanisms involved in this process remain unclear, with contradicting reports. Here, we characterized the unwinding dynamics of the Caenorhabditis elegans RecQ helicase HIM-6 using single-molecule fluorescence resonance energy transfer measurements. We found that HIM-6 exhibits reiterative DNA unwinding and the length of DNA unwound by the helicase is sharply defined at 25–31 bp. Experiments using various DNA substrates revealed that HIM-6 utilizes the mode of ‘sliding back’ on the translocated strand, without strand-switching for rewinding. Furthermore, we found that Caenorhabditis elegans replication protein A, a single-stranded DNA binding protein, suppresses the reiterative behavior of HIM-6 and induces unidirectional, processive unwinding, possibly through a direct interaction between the proteins. Our findings shed new light on the mechanism of DNA unwinding by RecQ family helicases and their co-operation with RPA in processing DNA.

scholarly journals Roles of the Bloom's syndrome helicase in the maintenance of genome stability

2005 ◽  
Vol 33 (6) ◽  
pp. 1456-1459 ◽  
Author(s):  
C.F. Cheok ◽  
C.Z. Bachrati ◽  
K.L. Chan ◽  
C. Ralf ◽  
L. Wu ◽  
...  
Keyword(s):  
Genome Stability ◽  
Protein A ◽  
Sister Chromatid Exchanges ◽  
Premature Aging ◽  
Bloom's Syndrome ◽  
Dna Helicases ◽  
Bloom’S Syndrome ◽  
Recombination Repair ◽  
Rothmund Thomson Syndrome ◽  
Chromatid Exchanges

The RecQ family of DNA helicases is highly conserved in evolution from bacteria to humans. Of the five known human RecQ family members, three (BLM, WRN and RECQ4, which cause Bloom's syndrome, Werner's syndrome and Rothmund–Thomson syndrome respectively) are mutated in distinct clinical disorders associated with cancer predisposition and/or premature aging. BLM forms part of a multienzyme complex including topoisomerase IIIα, replication protein A and a newly identified factor called BLAP75. Together, these proteins play a role in the resolution of DNA structures that arise during the process of homologous recombination repair. In the absence of BLM, cells show genomic instability and a high incidence of sister-chromatid exchanges. In addition to a DNA structure-specific helicase activity, BLM also catalyses Holliday-junction branch migration and the annealing of complementary single-stranded DNA molecules.

scholarly journals Bloom syndrome helicase contributes to germ line development and longevity in zebrafish

2021 ◽  
Author(s):  
Tamás Annus ◽  
Dalma Müller ◽  
Bálint Jezsó ◽  
György Ullaga ◽  
Gábor M. Harami ◽  
...  
Keyword(s):  
Dna Repair ◽  
Germ Line ◽  
Sex Differentiation ◽  
Disease Model ◽  
Bloom Syndrome ◽  
Recq Helicase ◽  
Genome Maintenance ◽  
Recq Helicases ◽  
Increased Risk

RecQ helicases - also known as the ‘guardians of the genome’ - play crucial roles in genome integrity maintenance through their involvement in various DNA metabolic pathways. Aside from being conserved from bacteria to vertebrates, their importance is also reflected in the fact that in humans impaired function of multiple RecQ helicase orthologs are known to cause severe sets of problems, including Bloom, Werner or Rothmund-Thomson syndromes. Our aim was to create and characterize a zebrafish (Danio rerio) disease model for Bloom syndrome, a recessive autosomal disorder. In humans, this syndrome is characterized by short stature, skin rashes, reduced fertility, increased risk of carcinogenesis and shortened life expectancy brought on by genomic instability. We show that zebrafish blm mutants recapitulate major hallmarks of the human disease, such as shortened lifespan and reduced fertility. Moreover, similarly to other factors involved in DNA repair, some functions of zebrafish Blm bear additional importance in germ line development, and consequently in sex differentiation. Unlike fanc genes and rad51, however, blm appears to effect its function independent of tp53. Therefore, our model will be a valuable tool for further understanding the developmental and molecular attributes of this rare disease, along with providing novel insights into the role of genome maintenance proteins in somatic DNA repair and fertility.

scholarly journals Human RecQ Helicases in DNA Double-Strand Break Repair

2021 ◽  
Vol 9 ◽  
Author(s):  
Huiming Lu ◽  
Anthony J. Davis
Keyword(s):  
Werner Syndrome ◽  
Genetic Disorders ◽  
Strand Break ◽  
Bloom Syndrome ◽  
Double Strand Break ◽  
Premature Aging ◽  
Telomere Maintenance ◽  
Dsb Repair ◽  
Recq Helicases ◽  
Dna Double Strand Break

RecQ DNA helicases are a conserved protein family found in bacteria, fungus, plants, and animals. These helicases play important roles in multiple cellular functions, including DNA replication, transcription, DNA repair, and telomere maintenance. Humans have five RecQ helicases: RECQL1, Bloom syndrome protein (BLM), Werner syndrome helicase (WRN), RECQL4, and RECQL5. Defects in BLM and WRN cause autosomal disorders: Bloom syndrome (BS) and Werner syndrome (WS), respectively. Mutations in RECQL4 are associated with three genetic disorders, Rothmund–Thomson syndrome (RTS), Baller–Gerold syndrome (BGS), and RAPADILINO syndrome. Although no genetic disorders have been reported due to loss of RECQL1 or RECQL5, dysfunction of either gene is associated with tumorigenesis. Multiple genetically independent pathways have evolved that mediate the repair of DNA double-strand break (DSB), and RecQ helicases play pivotal roles in each of them. The importance of DSB repair is supported by the observations that defective DSB repair can cause chromosomal aberrations, genomic instability, senescence, or cell death, which ultimately can lead to premature aging, neurodegeneration, or tumorigenesis. In this review, we will introduce the human RecQ helicase family, describe in detail their roles in DSB repair, and provide relevance between the dysfunction of RecQ helicases and human diseases.

Organization of Chromosome Ends in Ustilago maydis. RecQ-like Helicase Motifs at Telomeric Regions

Genetics ◽  
1998 ◽  
Vol 148 (3) ◽  
pp. 1043-1054 ◽  
Author(s):  
Patricia Sánchez-Alonso ◽  
Plinio Guzmán
Keyword(s):  
Nucleotide Sequence ◽  
Dna Sequences ◽  
Genome Stability ◽  
General Structure ◽  
Ustilago Maydis ◽  
Recq Helicase ◽  
Repeated Dna ◽  
Dna Helicases ◽  
Reading Frame ◽  
Recq Helicases

Abstract In this study we have established the structure of chromosome ends in the basidiomycete fungus Ustilago maydis. We isolated and characterized several clones containing telomeric regions and found that as in other organisms, they consist of middle repeated DNA sequences. Two principal types of sequence were found: UTASa was highly conserved in nucleotide sequence and located almost exclusively at the chromosome ends, and UTASb was less conserved in nucleotide sequence than UTASa and found not just at the ends but highly interspersed throughout the genome. Sequence analysis revealed that UTASa encodes an open reading frame containing helicase motifs with the strongest homology to RecQ helicases; these are DNA helicases whose function involves the maintenance of genome stability in Saccharomyces cerevisiae and in humans, and the suppression of illegitimate recombination in Escherichia coli. Both UTASa and UTASb contain a common region of about 300 bp located immediately adjacent to the telomere repeats that are also found interspersed in the genome. The analysis of the chromosome ends of U. maydis provides information on the general structure of chromosome ends in eukaryotes, and the putative RecQ helicase at UTASa may reveal a novel mechanism for the maintenance of chromosome stability.

Human RecQ helicases in transcription-associated stress management: bridging the gap between DNA and RNA metabolism

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Tulika Das ◽  
Surasree Pal ◽  
Agneyo Ganguly
Keyword(s):  
Genome Integrity ◽  
Complex Structures ◽  
Huge Number ◽  
Dna Helicases ◽  
Dna Structures ◽  
Recq Helicases ◽  
Dna And Rna ◽  
Cellular Dna ◽  
Almost All ◽  
Transcription And Replication

Abstract RecQ helicases are a highly conserved class of DNA helicases that play crucial role in almost all DNA metabolic processes including replication, repair and recombination. They are able to unwind a wide variety of complex intermediate DNA structures that may result from cellular DNA transactions and hence assist in maintaining genome integrity. Interestingly, a huge number of recent reports suggest that many of the RecQ family helicases are directly or indirectly involved in regulating transcription and gene expression. On one hand, they can remove complex structures like R-loops, G-quadruplexes or RNA:DNA hybrids formed at the intersection of transcription and replication. On the other hand, emerging evidence suggests that they can also regulate transcription by directly interacting with RNA polymerase or recruiting other protein factors that may regulate transcription. This review summarizes the up to date knowledge on the involvement of three human RecQ family proteins BLM, WRN and RECQL5 in transcription regulation and management of transcription associated stress.

scholarly journals Non-B DNA Secondary Structures and Their Resolution by RecQ Helicases

2011 ◽  
Vol 2011 ◽  
pp. 1-15 ◽  
Author(s):  
Sudha Sharma
Keyword(s):  
Transcriptional Control ◽  
Molecular Targets ◽  
Secondary Structures ◽  
Special Focus ◽  
Dna Helicases ◽  
Dna Structures ◽  
Recq Helicases ◽  
Alternative Structures ◽  
Dna Secondary Structures ◽  
Secondary Dna Structures

In addition to the canonical B-form structure first described by Watson and Crick, DNA can adopt a number of alternative structures. These non-B-form DNA secondary structures form spontaneously on tracts of repeat sequences that are abundant in genomes. In addition, structured forms of DNA with intrastrand pairing may arise on single-stranded DNA produced transiently during various cellular processes. Such secondary structures have a range of biological functions but also induce genetic instability. Increasing evidence suggests that genomic instabilities induced by non-B DNA secondary structures result in predisposition to diseases. Secondary DNA structures also represent a new class of molecular targets for DNA-interactive compounds that might be useful for targeting telomeres and transcriptional control. The equilibrium between the duplex DNA and formation of multistranded non-B-form structures is partly dependent upon the helicases that unwind (resolve) these alternate DNA structures. With special focus on tetraplex, triplex, and cruciform, this paper summarizes the incidence of non-B DNA structures and their association with genomic instability and emphasizes the roles of RecQ-like DNA helicases in genome maintenance by resolution of DNA secondary structures. In future, RecQ helicases are anticipated to be additional molecular targets for cancer chemotherapeutics.

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