The Experts below are selected from a list of 2334 Experts worldwide ranked by ideXlab platform
Michelle Debatisse - One of the best experts on this subject based on the ideXlab platform.
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pyrimidine pool imbalance induced by blm helicase deficiency contributes to genetic instability in Bloom Syndrome
Nature Communications, 2011Co-Authors: Pauline Chabosseau, Geraldine Buhagiarlabarchede, Rosine Onclercqdelic, Sarah Lambert, Michelle Debatisse, Olivier BrisonAbstract:Defects in DNA replication are associated with genetic instability and cancer development, as illustrated in Bloom Syndrome. Features of this Syndrome include a slowdown in replication speed, defective fork reactivation and high rates of sister chromatid exchange, with a general predisposition to cancer. Bloom Syndrome is caused by mutations in the BLM gene encoding a RecQ helicase. Here we report that BLM deficiency is associated with a strong cytidine deaminase defect, leading to pyrimidine pool disequilibrium. In BLM-deficient cells, pyrimidine pool normalization leads to reduction of sister chromatid exchange frequency and is sufficient for full restoration of replication fork velocity but not the fork restart defect, thus identifying the part of the Bloom Syndrome phenotype because of pyrimidine pool imbalance. This study provides new insights into the molecular basis of control of replication speed and the genetic instability associated with Bloom Syndrome. Nucleotide pool disequilibrium could be a general phenomenon in a large spectrum of precancerous and cancer cells.
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pyrimidine pool imbalance induced by blm helicase deficiency contributes to genetic instability in Bloom Syndrome
Nature Communications, 2011Co-Authors: Pauline Chabosseau, Geraldine Buhagiarlabarchede, Rosine Onclercqdelic, Sarah Lambert, Michelle DebatisseAbstract:Mutations in the DNA helicase BLM cause Bloom Syndrome, which is characterized by slow replication fork progression and genetic instability. Here, cells lacking BLM are shown to have a defect in cytidine deaminase, which alters the pyrimidine pool and results in replication fork progression with altered velocity.
Pauline Chabosseau - One of the best experts on this subject based on the ideXlab platform.
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pyrimidine pool imbalance induced by blm helicase deficiency contributes to genetic instability in Bloom Syndrome
Nature Communications, 2011Co-Authors: Pauline Chabosseau, Geraldine Buhagiarlabarchede, Rosine Onclercqdelic, Sarah Lambert, Michelle Debatisse, Olivier BrisonAbstract:Defects in DNA replication are associated with genetic instability and cancer development, as illustrated in Bloom Syndrome. Features of this Syndrome include a slowdown in replication speed, defective fork reactivation and high rates of sister chromatid exchange, with a general predisposition to cancer. Bloom Syndrome is caused by mutations in the BLM gene encoding a RecQ helicase. Here we report that BLM deficiency is associated with a strong cytidine deaminase defect, leading to pyrimidine pool disequilibrium. In BLM-deficient cells, pyrimidine pool normalization leads to reduction of sister chromatid exchange frequency and is sufficient for full restoration of replication fork velocity but not the fork restart defect, thus identifying the part of the Bloom Syndrome phenotype because of pyrimidine pool imbalance. This study provides new insights into the molecular basis of control of replication speed and the genetic instability associated with Bloom Syndrome. Nucleotide pool disequilibrium could be a general phenomenon in a large spectrum of precancerous and cancer cells.
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pyrimidine pool imbalance induced by blm helicase deficiency contributes to genetic instability in Bloom Syndrome
Nature Communications, 2011Co-Authors: Pauline Chabosseau, Geraldine Buhagiarlabarchede, Rosine Onclercqdelic, Sarah Lambert, Michelle DebatisseAbstract:Mutations in the DNA helicase BLM cause Bloom Syndrome, which is characterized by slow replication fork progression and genetic instability. Here, cells lacking BLM are shown to have a defect in cytidine deaminase, which alters the pyrimidine pool and results in replication fork progression with altered velocity.
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The Bloom Syndrome Protein Limits the Lethality Associated with RAD51 Deficiency
Molecular Cancer Research, 2010Co-Authors: Kenza Lahkim Bennani-belhaj, Emilie Bayart, Pauline Chabosseau, Sébastien Rouzeau, Géraldine Buhagiar-labarchède, Rosine Onclercq-delic, Fabrice Cordelières, Jérôme Couturier, Mounira Amor-guéretAbstract:Little is known about the functional interaction between the Bloom's Syndrome protein (BLM) and the recombinase RAD51 within cells. Using RNA interference technology, we provide the first demonstration that RAD51 acts upstream from BLM to prevent anaphase bridge formation. RAD51 downregulation was associated with an increase in the frequency of BLM-positive anaphase bridges, but not of BLM-associated ultrafine bridges. Time-lapse live microscopy analysis of anaphase bridge cells revealed that BLM promoted cell survival in the absence of Rad51. Our results directly implicate BLM in limiting the lethality associated with RAD51 deficiency through the processing of anaphase bridges resulting from the RAD51 defect. These findings provide insight into the molecular basis of some cancers possibly associated with variants of the RAD51 gene family.
Kristina H Schmidt - One of the best experts on this subject based on the ideXlab platform.
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a novel cell cycle regulated interaction of the Bloom Syndrome helicase blm with mcm6 controls replication linked processes
Nucleic Acids Research, 2021Co-Authors: Vivek M Shastri, Veena Subramanian, Kristina H SchmidtAbstract:The Bloom Syndrome DNA helicase BLM contributes to chromosome stability through its roles in double-strand break repair by homologous recombination and DNA replication fork restart during the replication stress response. Loss of BLM activity leads to Bloom Syndrome, which is characterized by extraordinary cancer risk and small stature. Here, we have analyzed the composition of the BLM complex during unperturbed S-phase and identified a direct physical interaction with the Mcm6 subunit of the minichromosome maintenance (MCM) complex. Using distinct binding sites, BLM interacts with the N-terminal domain of Mcm6 in G1 phase and switches to the C-terminal Cdt1-binding domain of Mcm6 in S-phase, with a third site playing a role for Mcm6 binding after DNA damage. Disruption of Mcm6-binding to BLM in S-phase leads to supra-normal DNA replication speed in unperturbed cells, and the helicase activity of BLM is required for this increased replication speed. Upon disruption of BLM/Mcm6 interaction, repair of replication-dependent DNA double-strand breaks is delayed and cells become hypersensitive to DNA damage and replication stress. Our findings reveal that BLM not only plays a role in the response to DNA damage and replication stress, but that its physical interaction with Mcm6 is required in unperturbed cells, most notably in S-phase as a negative regulator of replication speed.
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Bloom Syndrome dna helicase deficiency is associated with oxidative stress and mitochondrial network changes
Scientific Reports, 2021Co-Authors: Veena Subramanian, Vivek M Shastri, Brian Rodemoyer, Lene Juel Rasmussen, Claus Desler, Kristina H SchmidtAbstract:Bloom Syndrome (BS; OMIM #210900; ORPHA #125) is a rare genetic disorder that is associated with growth deficits, compromised immune system, insulin resistance, genome instability and extraordinary predisposition to cancer. Most efforts thus far have focused on understanding the role of the Bloom Syndrome DNA helicase BLM as a recombination factor in maintaining genome stability and suppressing cancer. Here, we observed increased levels of reactive oxygen species (ROS) and DNA base damage in BLM-deficient cells, as well as oxidative-stress-dependent reduction in DNA replication speed. BLM-deficient cells exhibited increased mitochondrial mass, upregulation of mitochondrial transcription factor A (TFAM), higher ATP levels and increased respiratory reserve capacity. Cyclin B1, which acts in complex with cyclin-dependent kinase CDK1 to regulate mitotic entry and associated mitochondrial fission by phosphorylating mitochondrial fission protein Drp1, fails to be fully degraded in BLM-deficient cells and shows unscheduled expression in G1 phase cells. This failure to degrade cyclin B1 is accompanied by increased levels and persistent activation of Drp1 throughout mitosis and into G1 phase as well as mitochondrial fragmentation. This study identifies mitochondria-associated abnormalities in Bloom Syndrome patient-derived and BLM-knockout cells and we discuss how these abnormalities may contribute to Bloom Syndrome.
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cellular defects caused by hypomorphic variants of the Bloom Syndrome helicase gene blm
Molecular Genetics & Genomic Medicine, 2016Co-Authors: Vivek M Shastri, Kristina H SchmidtAbstract:Background Bloom Syndrome is an autosomal recessive disorder characterized by extraordinary cancer incidence early in life and an average life expectancy of ~27 years. Premature stop codons in BLM, which encodes a DNA helicase that functions in DNA double-strand-break repair, make up the vast majority of Bloom Syndrome mutations, with only 13 single amino acid changes identified in the Syndrome. Sequencing projects have identified nearly one hundred single nucleotide variants in BLM that cause amino acid changes of uncertain significance. Methods and Results Here, in addition to identifying five BLM variants incapable of complementing certain defects of Bloom Syndrome cells, making them candidates for new Bloom Syndrome causing mutations, we characterize a new class of BLM variants that cause some, but not all, cellular defects of Bloom Syndrome. We find elevated sister-chromatid exchanges, a delayed DNA damage response and inefficient DNA repair. Conversely, hydroxyurea sensitivity and quadriradial chromosome accumulation, both characteristic of Bloom Syndrome cells, are absent. These intermediate variants affect sites in BLM that function in ATP hydrolysis and in contacting double-stranded DNA. Conclusion Allele frequency and cellular defects suggest candidates for new Bloom Syndrome causing mutations, and intermediate BLM variants that are hypomorphic which, instead of causing Bloom Syndrome, may increase a person's risk for cancer or possibly other Bloom-Syndrome-associated disorders, such as type-2 diabetes.
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non Bloom Syndrome associated partial and total loss of function variants of blm helicase
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Hamed Mirzaei, Kristina H SchmidtAbstract:Bloom Syndrome (BS) is an autosomal recessive disorder caused by mutations in the RecQ-like DNA helicase BLM, which functions in the maintenance of genome stability. Using a humanized model of Saccharomyces cerevisiae that expresses a chimera of the N terminus of yeast Sgs1 and the C terminus of human BLM from the chromosomal SGS1 locus, we have functionally evaluated 27 BLM alleles that are not currently known to be associated with BS. We identified nine alleles with impaired function when assessed for hypersensitivity to the DNA-damaging agent hydroxyurea (HU). Six of these alleles (P690L, R717T, W803R, Y811C, F857L, G972V) caused sensitivity to HU that was comparable to known BS-associated or helicase-dead alleles, suggesting that they may cause BS and, in the heterozygous state, act as risk factors for cancerogenesis. We also identified three alleles (R791C, P868L, G1120R) that caused intermediate sensitivity to HU; although unlikely to cause BS, these partial loss-of-function alleles may increase risk for cancers or other BS-associated complications if a person is homozygous or compound heterozygous for these alleles or if they carry a known BS-associated allele.
Weidong Wang - One of the best experts on this subject based on the ideXlab platform.
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identification and analysis of new proteins involved in the dna damage response network of fanconi anemia and Bloom Syndrome
Methods, 2009Co-Authors: Rong Guo, Weidong WangAbstract:The use of co-immunoprecipitation (co-IP) to purify multi-protein complexes has contributed greatly to our understanding of the DNA damage response network associated with Fanconi anemia (FA), Bloom Syndrome (BS) and breast cancer. Four new FA genes and two new protein partners for the Bloom Syndrome gene product have been identified by co-IP. Here, we discuss our experience in using co-IP and other techniques to isolate and characterize new FA and BS-related proteins.
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emergence of a dna damage response network consisting of fanconi anaemia and brca proteins
Nature Reviews Genetics, 2007Co-Authors: Weidong WangAbstract:Fanconi anaemia (FA) has recently become an attractive model to study breast cancer susceptibility (BRCA) genes, as three FA genes, FANCD1, FANCN and FANCJ, are identical to the BRCA genes BRCA2, PALB2 and BRIP1. Increasing evidence shows that FA proteins function as signal transducers and DNA-processing molecules in a DNA-damage response network. This network consists of many proteins that maintain genome integrity, including ataxia telangiectasia and Rad3 related protein (ATR), Bloom Syndrome protein (BLM), and BRCA1. Now that the gene that is defective in the thirteenth and last assigned FA complementation group (FANCI) has been identified, I discuss what is known about FA proteins and their interactive network, and what remains to be discovered.
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a multiprotein nuclear complex connects fanconi anemia and Bloom Syndrome
Molecular and Cellular Biology, 2003Co-Authors: Amom Ruhikanta Meetei, Salvatore Sechi, Michael Wallisch, Dafeng Yang, Mary K Young, Hans Joenje, Maureen E Hoatlin, Weidong WangAbstract:Bloom Syndrome (BS) is a genetic disorder associated with dwarfism, immunodeficiency, reduced fertility, and an elevated risk of cancer. To investigate the mechanism of this disease, we isolated from human HeLa extracts three complexes containing the helicase defective in BS, BLM. Interestingly, one of the complexes, termed BRAFT, also contains five of the Fanconi anemia (FA) complementation group proteins (FA proteins). FA resembles BS in genomic instability and cancer predisposition, but most of its gene products have no known biochemical activity, and the molecular pathogenesis of the disease is poorly understood. BRAFT displays a DNA-unwinding activity, which requires the presence of BLM because complexes isolated from BLM-deficient cells lack such an activity. The complex also contains topoisomerase IIIα and replication protein A, proteins that are known to interact with BLM and could facilitate unwinding of DNA. We show that BLM complexes isolated from an FA cell line have a lower molecular mass. Our study provides the first biochemical characterization of a multiprotein FA complex and suggests a connection between the BLM and FA pathways of genomic maintenance. The findings that FA proteins are part of a DNA-unwinding complex imply that FA proteins may participate in DNA repair.
Geraldine Buhagiarlabarchede - One of the best experts on this subject based on the ideXlab platform.
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pyrimidine pool imbalance induced by blm helicase deficiency contributes to genetic instability in Bloom Syndrome
Nature Communications, 2011Co-Authors: Pauline Chabosseau, Geraldine Buhagiarlabarchede, Rosine Onclercqdelic, Sarah Lambert, Michelle Debatisse, Olivier BrisonAbstract:Defects in DNA replication are associated with genetic instability and cancer development, as illustrated in Bloom Syndrome. Features of this Syndrome include a slowdown in replication speed, defective fork reactivation and high rates of sister chromatid exchange, with a general predisposition to cancer. Bloom Syndrome is caused by mutations in the BLM gene encoding a RecQ helicase. Here we report that BLM deficiency is associated with a strong cytidine deaminase defect, leading to pyrimidine pool disequilibrium. In BLM-deficient cells, pyrimidine pool normalization leads to reduction of sister chromatid exchange frequency and is sufficient for full restoration of replication fork velocity but not the fork restart defect, thus identifying the part of the Bloom Syndrome phenotype because of pyrimidine pool imbalance. This study provides new insights into the molecular basis of control of replication speed and the genetic instability associated with Bloom Syndrome. Nucleotide pool disequilibrium could be a general phenomenon in a large spectrum of precancerous and cancer cells.
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pyrimidine pool imbalance induced by blm helicase deficiency contributes to genetic instability in Bloom Syndrome
Nature Communications, 2011Co-Authors: Pauline Chabosseau, Geraldine Buhagiarlabarchede, Rosine Onclercqdelic, Sarah Lambert, Michelle DebatisseAbstract:Mutations in the DNA helicase BLM cause Bloom Syndrome, which is characterized by slow replication fork progression and genetic instability. Here, cells lacking BLM are shown to have a defect in cytidine deaminase, which alters the pyrimidine pool and results in replication fork progression with altered velocity.