RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1

Genome instability is associated with myriad human diseases and is a well-known feature of both cancer and neurodegenerative disease. Until recently, the ability to assess DNA damage—the principal driver of genome instability—was limited to relatively imprecise methods or restricted to studying predefined genomic regions. Recently, new techniques for detecting DNA double strand breaks (DSBs) and single strand breaks (SSBs) with next-generation sequencing on a genome-wide scale with single nucleotide resolution have emerged. With these new tools, efforts are underway to define the “breakome” in normal aging and disease. Here, we compare the relative strengths and weaknesses of these technologies and their potential application to studying neurodegenerative diseases.

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DisA limits RecA- and RadA/Sms-mediated replication fork remodelling to prevent genome instability

10.1101/2020.11.23.394155 ◽

2020 ◽

Author(s):

Rubén Torres ◽

Juan C. Alonso

Keyword(s):

Genome Instability ◽

Dna Helicase ◽

Template Switching ◽

Replication Forks ◽

Lesion Bypass ◽

Branched Dna ◽

Subject Categories ◽

Negative Effect ◽

Dna Replication Stress ◽

Stalled Replication Forks

AbstractThe DisA diadenylate cyclase (DAC), the DNA helicase RadA/Sms and the RecA recombinase are required to prevent a DNA replication stress during the revival of haploid Bacillus subtilis spores. Moreover, disA, radA and recA are epistatic among them in response to DNA damage. We show that DisA inhibits the ATPase activity of RadA/Sms C13A by competing for single-stranded (ss) DNA. In addition, DisA inhibits the helicase activity of RadA/Sms. RecA filamented onto ssDNA interacts with and recruits DisA and RadA/Sms onto branched DNA intermediates. In fact, RecA binds a reversed fork and facilitates RadA/Sms-mediated unwinding to restore a 3′-fork intermediate, but DisA inhibits it. Finally, RadA/Sms inhibits DisA DAC activity, but RecA counters this negative effect. We propose that RecA, DisA and RadA/Sms interactions, which are mutually exclusive, limit remodelling of stalled replication forks. DisA, in concert with RecA and/or RadA/Sms, indirectly contributes to template switching or lesion bypass, prevents fork breakage and facilitates the recovery of c-di-AMP levels to re-initiate cell proliferation.Subject CategoriesGenomic stability & Dynamics

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Maintenance of Yeast Genome Integrity by RecQ Family DNA Helicases

Genes ◽

10.3390/genes11020205 ◽

2020 ◽

Vol 11 (2) ◽

pp. 205 ◽

Cited By ~ 5

Author(s):

Sonia Vidushi Gupta ◽

Kristina Hildegard Schmidt

Keyword(s):

Genome Instability ◽

Dna Helicase ◽

Model Systems ◽

Yeast Cells ◽

Genome Integrity ◽

Yeast Genome ◽

Physical Interaction ◽

Recq Helicase ◽

Recq Helicases ◽

Domain Structures

With roles in DNA repair, recombination, replication and transcription, members of the RecQ DNA helicase family maintain genome integrity from bacteria to mammals. Mutations in human RecQ helicases BLM, WRN and RecQL4 cause incurable disorders characterized by genome instability, increased cancer predisposition and premature adult-onset aging. Yeast cells lacking the RecQ helicase Sgs1 share many of the cellular defects of human cells lacking BLM, including hypersensitivity to DNA damaging agents and replication stress, shortened lifespan, genome instability and mitotic hyper-recombination, making them invaluable model systems for elucidating eukaryotic RecQ helicase function. Yeast and human RecQ helicases have common DNA substrates and domain structures and share similar physical interaction partners. Here, we review the major cellular functions of the yeast RecQ helicases Sgs1 of Saccharomyces cerevisiae and Rqh1 of Schizosaccharomyces pombe and provide an outlook on some of the outstanding questions in the field.

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Computational identification of mutator-derived lncRNA signatures of genome instability for improving the clinical outcome of cancers: a case study in breast cancer

Briefings in Bioinformatics ◽

10.1093/bib/bbz118 ◽

2019 ◽

Vol 21 (5) ◽

pp. 1742-1755 ◽

Cited By ~ 26

Author(s):

Siqi Bao ◽

Hengqiang Zhao ◽

Jian Yuan ◽

Dandan Fan ◽

Zicheng Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Genomic Instability ◽

Genome Instability ◽

Risk Group ◽

Expression Profiles ◽

Risk Groups ◽

Low Risk ◽

A Genome ◽

Significant Difference

Abstract Emerging evidence revealed the critical roles of long non-coding RNAs (lncRNAs) in maintaining genomic instability. However, identification of genome instability-associated lncRNAs and their clinical significance in cancers remain largely unexplored. Here, we developed a mutator hypothesis-derived computational frame combining lncRNA expression profiles and somatic mutation profiles in a tumor genome and identified 128 novel genomic instability-associated lncRNAs in breast cancer as a case study. We then identified a genome instability-derived two lncRNA-based gene signature (GILncSig) that stratified patients into high- and low-risk groups with significantly different outcome and was further validated in multiple independent patient cohorts. Furthermore, the GILncSig correlated with genomic mutation rate in both ovarian cancer and breast cancer, indicating its potential as a measurement of the degree of genome instability. The GILncSig was able to divide TP53 wide-type patients into two risk groups, with the low-risk group showing significantly improved outcome and the high-risk group showing no significant difference compared with those with TP53 mutation. In summary, this study provided a critical approach and resource for further studies examining the role of lncRNAs in genome instability and introduced a potential new avenue for identifying genomic instability-associated cancer biomarkers.

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BCR/ABL Regulates the Expression and Interacts with Werner Syndrome Helicase/Exonuclease To Modulate Its Biochemical Properties.

Blood ◽

10.1182/blood.v106.11.2873.2873 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2873-2873

Author(s):

Artur Slupianek ◽

Stanislaw Jozwiakowski ◽

Ewa Gurdek ◽

Michal O. Nowicki ◽

Tomasz Skorski

Keyword(s):

Werner Syndrome ◽

Genotoxic Stress ◽

Biochemical Properties ◽

Dna Helicase ◽

Premature Aging ◽

Leukemia Cells ◽

Dna Double Strand Breaks ◽

Abl Kinase ◽

A Genome ◽

Transformed Cell Lines

Abstract A genome-wide screen suggested that BCR/ABL kinase might stimulate WRN, a member of the RecQ-like DNA helicases family. The Werner syndrome protein (WRN) exerts DNA helicase and 3′-5′ exonuclease activities. Inactivating mutations in the WRN gene causes Werner syndrome, characterized by premature aging, genomic instability and cancer predisposition. The WRN helicase unwinds unusual DNA structures, which can occur physiologically, or can be accidentally generated during DNA repair (double-stranded DNA with mismatched tails, bimolecular G4 quartets and Holliday junctions). In addition, WRN physically interacts with components of two major systems for DNA double-strand breaks (DSBs) repair: non-homologous end-joining (NHEJ) and homologous recombination (HR). Here we demonstrated that BCR/ABL regulates the expression of WRN mRNA and protein in CML primary cells and BCR/ABL-transformed cell lines. BCR/ABL kinase-induced WRN expression is mediated by c-MYC, but not STAT5 - dependent transcription as well as by inhibition of caspases-dependent cleavage. In addition, immunoprecipitation and pull-down studies indicated that BCR/ABL interacts directly with WRN resulting in its tyrosine phosphorylation. Mutation analysis revealed that multiple domains/amino acid residues of BCR/ABL and WRN are involved in the interaction. BCR/ABL-positive leukemia cells exerted an enhanced WRN-dependent helicase activity. In addition, immunoprecipitation and double-immunofluorescence co-localization studies demonstrated an elevated interaction between WRN and RAD51 in BCR/ABL cells undergoing genotoxic stress in comparison to parental counterparts. Altogether, it is likely that WRN is involved in DSBs repair by HR in leukemia cells. More detailed studies are underway to pinpoint the role of WRN in DNA damage response in BCR/ABL-transformed cells.

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Functional and Physical Interaction of Yeast Mgs1 with PCNA: Impact on RAD6-Dependent DNA Damage Tolerance

Molecular and Cellular Biology ◽

10.1128/mcb.00307-06 ◽

2006 ◽

Vol 26 (14) ◽

pp. 5509-5517 ◽

Cited By ~ 48

Author(s):

Takashi Hishida ◽

Tomoko Ohya ◽

Yoshino Kubota ◽

Yusuke Kamada ◽

Hideo Shinagawa

Keyword(s):

Dna Damage ◽

Posttranslational Modifications ◽

Cell Cycle Progression ◽

Damage Tolerance ◽

Genome Instability ◽

Dna Helicase ◽

Nuclear Antigen ◽

Physical Interaction ◽

Dna Damage Tolerance ◽

Exogenous Dna

ABSTRACT Proliferating cell nuclear antigen (PCNA), a sliding clamp required for processive DNA synthesis, provides attachment sites for various other proteins that function in DNA replication, DNA repair, cell cycle progression and chromatin assembly. It has been shown that differential posttranslational modifications of PCNA by ubiquitin or SUMO play a pivotal role in controlling the choice of pathway for rescuing stalled replication forks. Here, we explored the roles of Mgs1 and PCNA in replication fork rescue. We provide evidence that Mgs1 physically associates with PCNA and that Mgs1 helps suppress the RAD6 DNA damage tolerance pathway in the absence of exogenous DNA damage. We also show that PCNA sumoylation inhibits the growth of mgs1 rad18 double mutants, in which PCNA sumoylation and the Srs2 DNA helicase coordinately prevent RAD52-dependent homologous recombination. The proposed roles for Mgs1, Srs2, and modified PCNA during replication arrest highlight the importance of modulating the RAD6 and RAD52 pathways to avoid genome instability.

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Construction of a genome instability-derived lncRNA based risk scoring system for the prognosis of hepatocellular carcinoma

Aging ◽

10.18632/aging.203698 ◽

2021 ◽

Author(s):

Dan-Ping Huang ◽

Mian-Mian Liao ◽

Jing-Jing Tong ◽

Wei-Qu Yuan ◽

De-Ti Peng ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Scoring System ◽

Genome Instability ◽

A Genome ◽

Risk Scoring ◽

Risk Scoring System

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MRE11-RAD50-NBS1 activates Fanconi Anemia R-loop suppression at transcription-replication conflicts

10.1101/472654 ◽

2018 ◽

Author(s):

Emily Yun-chia Chang ◽

James P. Wells ◽

Shu-Huei Tsai ◽

Yan Coulombe ◽

Yujia A. Chan ◽

...

Keyword(s):

Dna Replication ◽

Fanconi Anemia ◽

Replication Fork ◽

Genome Instability ◽

Human Cancer ◽

Replication Stress ◽

Maintenance Factors ◽

Genome Wide ◽

A Genome ◽

Dna Replication Stress

SUMMARYEctopic R-loop accumulation causes DNA replication stress and genome instability. To avoid these outcomes, cells possess a range of anti-R-loop mechanisms, including RNaseH that degrades the RNA moiety in R-loops. To comprehensively identify anti-R-loop mechanisms, we performed a genome-wide trigenic interaction screen in yeast lacking RNH1 and RNH201. We identified >100 genes critical for fitness in the absence of RNaseH, which were enriched for DNA replication fork maintenance factors such as RAD50. We show in yeast and human cells that R-loops accumulate during RAD50 depletion. In human cancer cell models, we find that RAD50 and its partners in the MRE11-RAD50-NBS1 complex regulate R-loop-associated DNA damage and replication stress. We show that a non-nucleolytic function of MRE11 is important for R-loop suppression via activation of PCNA-ubiquitination by RAD18 and recruiting anti-R-loop helicases in the Fanconi Anemia pathway. This work establishes a novel role for MRE11-RAD50-NBS1 in directing tolerance mechanisms of transcription-replication conflicts.

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Identification of a Novel Prognostic Signature of Genome Instability-Related LncRNAs in Early Stage Lung Adenocarcinoma

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.706454 ◽

2021 ◽

Vol 9 ◽

Author(s):

Bo Peng ◽

Huawei Li ◽

Ruisi Na ◽

Tong Lu ◽

Yongchao Li ◽

...

Keyword(s):

High Risk ◽

Lung Adenocarcinoma ◽

Genomic Instability ◽

Cox Regression ◽

Genome Instability ◽

Early Stage ◽

Prognostic Signature ◽

Training Set ◽

A Genome ◽

Testing Set

BackgroundIncreasing evidence has demonstrated that long non-coding RNAs (lncRNAs) play a crucial part in maintaining genomic instability. We therefore identified genome instability-related lncRNAs and constructed a prediction signature for early stage lung adenocarcinoma (LUAD) as well in order for classification of high-risk group of patients and improvement of individualized therapies.MethodsEarly stage LUAD RNA-seq and clinical data from The Cancer Genome Atlas (TCGA) were randomly divided into training set (n = 177) and testing set (n = 176). A total of 146 genomic instability-associated lncRNAs were identified based on somatic mutation profiles combining lncRNA expression profiles from TCGA by the “limma R” package. We performed Cox regression analysis to develop this predictive indicator. We validated the prognostic signature by an external independent LUAD cohort with microarray platform acquired from the Gene Expression Omnibus (GEO).ResultsA genome instability-related six-lncRNA-based gene signature (GILncSig) was established to divide subjects into high-risk and low-risk groups with different outcomes at statistically significant levels. According to the multivariate Cox regression and stratification analysis, the GILncSig was an independent predictive factor. Furthermore, the six-lncRNA signature achieved AUC values of 0.745, 0.659, and 0.708 in the training set, testing set, and TCGA set, respectively. When compared with other prognostic lncRNA signatures, the GILncSig also exhibited better prediction performance.ConclusionThe prognostic lncRNA signature is a potent tool for risk stratification of early stage LUAD patients. Our study also provided new insights for identifying genome instability-related cancer biomarkers.

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Srs2 and Sgs1 DNA Helicases Associate with Mre11 in Different Subcomplexes following Checkpoint Activation and CDK1-Mediated Srs2 Phosphorylation

Molecular and Cellular Biology ◽

10.1128/mcb.25.13.5738-5751.2005 ◽

2005 ◽

Vol 25 (13) ◽

pp. 5738-5751 ◽

Cited By ~ 64

Author(s):

Irene Chiolo ◽

Walter Carotenuto ◽

Giulio Maffioletti ◽

John H. J. Petrini ◽

Marco Foiani ◽

...

Keyword(s):

Dna Damage ◽

Cellular Response ◽

Genome Instability ◽

Dna Recombination ◽

Dna Helicase ◽

Checkpoint Activation ◽

Dna Helicases ◽

Checkpoint Response ◽

Checkpoint Kinases ◽

Genes Encoding

ABSTRACT Mutations in the genes encoding the BLM and WRN RecQ DNA helicases and the MRE11-RAD50-NBS1 complex lead to genome instability and cancer predisposition syndromes. The Saccharomyces cerevisiae Sgs1 RecQ helicase and the Mre11 protein, together with the Srs2 DNA helicase, prevent chromosome rearrangements and are implicated in the DNA damage checkpoint response and in DNA recombination. By searching for Srs2 physical interactors, we have identified Sgs1 and Mre11. We show that Srs2, Sgs1, and Mre11 form a large complex, likely together with yet unidentified proteins. This complex reorganizes into Srs2-Mre11 and Sgs1-Mre11 subcomplexes following DNA damage-induced activation of the Mec1 and Tel1 checkpoint kinases. The defects in subcomplex formation observed in mec1 and tel1 cells can be recapitulated in srs2-7AV mutants that are hypersensitive to intra-S DNA damage and are altered in the DNA damage-induced and Cdk1-dependent phosphorylation of Srs2. Altogether our observations indicate that Mec1- and Tel1-dependent checkpoint pathways modulate the functional interactions between Srs2, Sgs1, and Mre11 and that the Srs2 DNA helicase represents an important target of the Cdk1-mediated cellular response induced by DNA damage.

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