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 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.

The role of BRCA1 in DNA repair and chemosensitivity

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10606-10606 ◽  
Author(s):  
V. B. Sharma ◽  
A. W. Kurian ◽  
A. Feldman ◽  
J. M. Ford
Keyword(s):  
Dna Repair ◽  
Oxidative Dna Damage ◽  
Excision Repair ◽  
Brca1 Gene ◽  
Brca1 Protein ◽  
P53 Expression ◽  
Increased Risk ◽  
Uv C

10606 Introduction: The BRCA1 tumor suppressor protein has been implicated in many cellular processes, including several different DNA repair pathways. Inherited mutations in the BRCA1 gene result in an increased risk for developing breast and ovarian cancer. BRCA1 associated tumors are frequently estrogen receptor negative thus rendering them ineffective targets of hormonal manipulations. Therefore chemotherapy is the only treatment option available to patients with metastatic disease. Methods: Global genomic repair activity was detected by an immunoslotblot assay. UV-C and chemosensitivity was determined by the MTT assay. The comet assay was used to measure oxidative DNA damage (ODD). Results: Brca1 deficient cells demonstrate decreased global genomic repair independent of p53 expression. These cells are 3-fold more sensitive to UV-C radiation, 5-fold more sensitive to cisplatin, and 25-fold more sensitive to gemcitabine than Brca1 positive cells. The combination of cisplatin and gemcitabine is synergistic. This synergy is independent of Brca1 protein expression. In addition, the cholesterol lowering drug lovastatin is able mitigate the ODD caused by hydrogen peroxide. Reduced ODD is also observed in breast epithelial cells from high risk patients after 6 months of oral lovastatin use. Discussion: These results confirm our earlier findings that BRCA1 is involved in the nucleotide excision repair pathway. In addition, we demonstrate that this effect is independent of p53 expression. We also find that Brca1 deficient MMECs are more sensitive to UV-C, and the cytotoxic drugs cisplatin and gemcitabine. Cisplatin is known to cause DNA intra- and inter-strand crosslinks whereas gemcitabine is a nucleoside analog. The increased sensitivity of Brca1 deficient MMEC's to these agents supports the role of Brca1 in the different molecular pathways involved in their repair. In addition, we demonstrate that lovastatin can overcome ODD in vitro and in vivo and may be an effective agent to modify breast cancer risk for individuals at increased risk. No significant financial relationships to disclose.

scholarly journals Functional conservation of RecQ helicase BLM between humans and Drosophila melanogaster

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Rebecca L. Cox ◽  
Carolyn M. Hofley ◽  
Pallavi Tatapudy ◽  
Romil K. Patel ◽  
Yaron Dayani ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Werner Syndrome ◽  
Genetic Diseases ◽  
Strand Break ◽  
Bloom Syndrome ◽  
Recq Helicase ◽  
Recq Helicases ◽  
Functional Conservation ◽  
Increased Sensitivity ◽  
Inherited Mutations

AbstractRecQ helicases are a family of proteins involved in maintaining genome integrity with functions in DNA repair, recombination, and replication. The human RecQ helicase family consists of five helicases: BLM, WRN, RECQL, RECQL4, and RECQL5. Inherited mutations in RecQ helicases result in Bloom Syndrome (BLM mutation), Werner Syndrome (WRN mutation), Rothmund-Thomson Syndrome (RECQL4 mutation), and other genetic diseases, including cancer. The RecQ helicase family is evolutionarily conserved, as Drosophila melanogaster have three family members: DmBlm, DmRecQL4, and DmRecQL5 and DmWRNexo, which contains a conserved exonuclease domain. DmBlm has functional similarities to human BLM (hBLM) as mutants demonstrate increased sensitivity to ionizing radiation (IR) and a decrease in DNA double-strand break (DSB) repair. To determine the extent of functional conservation of RecQ helicases, hBLM was expressed in Drosophila using the GAL4 > UASp system to determine if GAL4 > UASp::hBLM can rescue DmBlm mutant sensitivity to IR. hBLM was able to rescue female DmBlm mutant sensitivity to IR, supporting functional conservation. This functional conservation is specific to BLM, as human GAL4 > UASp::RECQL was not able to rescue DmBlm mutant sensitivity to IR. These results demonstrate the conserved role of BLM in maintaining the genome while reinforcing the applicability of using Drosophila as a model system to study Bloom Syndrome.

The Role of the XPF Gene Polymorphism (Xrcc4) Ser835ser in the Risk of Malignant Transformation of Cells in the Colorectal Cancer

2015 ◽  
Vol 87 (2) ◽  
Author(s):  
Jacek Kabziński ◽  
Ireneusz Majsterek ◽  
Adam Dziki ◽  
Michał Mik
Keyword(s):  
Colorectal Cancer ◽  
Dna Repair ◽  
Gene Polymorphism ◽  
Risk Groups ◽  
Control Group ◽  
Preventive Program ◽  
Increased Risk ◽  
Long Time ◽  
Repair Systems

AbstractParticipation of DNA repair systems in the pathogenesis of cancer has been a suspected phenomenon for a long time. Decreased efficiency in DNA repair translates to their ability to fix and consequently leads to mutations and the process of carcinogenesis. Linking individual polymorphisms of DNA repair systems with an increased risk of colorectal cancer will allow the classification of patients to high-risk groups and their placement under preventive program.The aim of the study was to determine the effect of XPF gene polymorphism Ser835Ser on increasing the risk of colorectal cancer in the Polish population.Material and methods. as the material blood collected from 146 patients diagnosed with colon cancer was used. The control group consisted of 149 healthy subjects. Genotyping was performed by Taq- Man method.Results. The results indicate that genotype TCC/TCT is associated with an decreased risk of colorectal cancer (OR 0.574; CI 95% 0.335-0.984; p=0.043).Conclusions. Based on these results, we conclude that the XPF gene polymorphism Ser835Ser may be associated with a decreased risk of colorectal cancer

scholarly journals The nuclear RNAi factor, NRDE2, prevents the accumulation of DNA damage during mitosis in stressful growth conditions

2018 ◽  
Author(s):  
Aarati Asundi ◽  
Srivats Venkataramanan ◽  
Gina Caldas Cuellar ◽  
Atsushi Suzuki ◽  
Stephen N. Floor ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Mammalian Cells ◽  
Germ Line ◽  
Repair Process ◽  
Growth Conditions ◽  
Filamentous Actin ◽  
Heterochromatin Formation ◽  
C Elegans ◽  
Increased Risk

AbstractOrganisms have evolved multiple mechanisms to prevent and repair DNA damage to protect the integrity of the genome, particularly under stressful conditions. Unrepaired DNA damage leads to genomic instability, aneuploidy, and an increased risk for cancer. Before the cell can divide, it must repair damaged DNA and it is thought that this process requires global silencing of most transcription. In C. elegans, NRDE-2, in complex with other nuclear factors and guided by small RNA, directs heterochromatin formation and transcriptional silencing of targeted genes. Additionally, when C. elegans are cultivated at high temperatures, NRDE-2 is required to maintain germ line immortality. However, the role of NRDE-2 in maintaining the physical integrity of the genome is not understood. We show here that loss of NRDE2 in either nematode or human cells induces the accumulation of DNA damage specifically under conditions of stress, such as cultivation at a high temperature in C. elegans or Aurora B Kinase oncogenic overexpression in the MCF10A epithelial breast cell line. In addition, we found that NRDE2 interacts with β-actin in unstressed mammalian cells. This interaction is dramatically reduced upon DNA damage. Monomeric nuclear actin binds to heterochromatin remodeling factors and transcriptional activators while filamentous actin has been implicated in DNA repair processes. Thus, NRDE2 may dissociate from actin when it becomes filamentous as a result of DNA damage. In this way, heterochromatin factors may associate with the actin dependent DNA repair process to allow appropriate mitotic progression and maintain genomic integrity.

scholarly journals Role for the Fission Yeast RecQ Helicase in DNA Repair in G2

2003 ◽  
Vol 23 (10) ◽  
pp. 3692-3705 ◽  
Author(s):  
Louise V. Laursen ◽  
Eleni Ampatzidou ◽  
Anni H. Andersen ◽  
Johanne M. Murray
Keyword(s):  
Dna Repair ◽  
Radiation Sensitivity ◽  
Recq Helicase ◽  
Focus Formation ◽  
High Molecular Weight Complex ◽  
Recq Helicases ◽  
Epistasis Analysis ◽  
Rad51 Focus ◽  
Human Genomic ◽  
Kinetics Of

ABSTRACT Members of the RecQ helicase subfamily are mutated in several human genomic instability syndromes, such as Bloom, Werner, and Rothmund-Thomson syndromes. We show that Rqh1, the single Schizosaccharomyces pombe homologue, is a 3′-to-5′ helicase and exists with Top3 in a high-molecular-weight complex. top3 deletion is inviable, and this is suppressed by concomitant loss of rqh1 helicase activity or loss of recombination functions. This is consistent with RecQ helicases in other systems. By using epistasis analysis of the UV radiation sensitivity and by analyzing the kinetics of Rhp51 (Rad51 homologue), Rqh1, and Top3 focus formation in response to UV in synchronized cells, we identify the first evidence of a function for Rqh1 and Top3 in the repair of UV-induced DNA damage in G2. Our data provide evidence that Rqh1 functions after Rad51 focus formation during DNA repair. We also identify a function for Rqh1 upstream of recombination in an Rhp18-dependent (Rad18 homologue) pathway. The model that these data allow us to propose helps to reconcile different interpretations of RecQ family helicase function that have arisen between work based on the S. pombe system and models based on studies of Saccharomyces cerevisiae SGS1 suggesting that RecQ helicases act before Rad51.

scholarly journals Role of Deubiquitinating Enzymes in DNA Repair

2015 ◽  
Vol 36 (4) ◽  
pp. 524-544 ◽  
Author(s):  
Younghoon Kee ◽  
Tony T Huang
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Mammalian Cells ◽  
Genome Stability ◽  
Regulatory Mechanisms ◽  
Deubiquitinating Enzymes ◽  
Genome Maintenance ◽  
Dna Damage Signaling ◽  
Damage Response

Both proteolytic and nonproteolytic functions of ubiquitination are essential regulatory mechanisms for promoting DNA repair and the DNA damage response in mammalian cells. Deubiquitinating enzymes (DUBs) have emerged as key players in the maintenance of genome stability. In this minireview, we discuss the recent findings on human DUBs that participate in genome maintenance, with a focus on the role of DUBs in the modulation of DNA repair and DNA damage signaling.

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