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The Israel Medical Association Journal... Dec 2007Fanconi anemia complementation group C and Bloom syndrome, rare autosomal recessive disorders marked by chromosome instability, are especially prevalent in the...
BACKGROUND
Fanconi anemia complementation group C and Bloom syndrome, rare autosomal recessive disorders marked by chromosome instability, are especially prevalent in the Ashkenazi* Jewish community. A single predominant mutation for each has been reported in Ahshkenazi Jews: c.711+4A-->T (IVS4 +4 A-->T) in FACC and BLM(Ash) in Bloom syndrome. Individuals affected by either of these syndromes are characterized by susceptibility for developing malignancies, and we questioned whether heterozygote carriers have a similarly increased risk.
OBJECTIVES
To estimate the cancer rate among FACC and BLM(Ash) carriers and their families over three previous generations in unselected Ashkenazi Jewish individuals.
METHODS
We studied 42 FACC carriers, 28 BLM(Ash) carriers and 43 controls. The control subjects were Ashkenazi Jews participating in our prenatal genetic screening program who tested negative for FACC and BLM(Ash). All subjects filled out a questionnaire regarding their own and a three-generation family history of cancer. The prevalence rates of cancer among relatives of FACC, BLM(Ash) and controls were computed and compared using the chi-square test.
RESULTS
In 463 relatives of FACC carriers, 45 malignancies were reported (9.7%) including 10 breast (2.2%) and 13 colon cancers (2.8%). Among 326 relatives of BLM(Ash) carriers there were 30 malignancies (9.2%) including 7 breast (2.1%) and 4 colon cancers (1.2%). Controls consisted of 503 family members with 63 reported malignancies (12.5%) including 11 breast (2.2%) and 11 colon cancers (2.2%).
CONCLUSIONS
We found no significantly increased prevalence of malignancies among carriers in at least three generations compared to the controls.
Topics: Adult; Bloom Syndrome; Breast Neoplasms; Case-Control Studies; Colorectal Neoplasms; Fanconi Anemia; Female; Heterozygote; Humans; Israel; Jews; Male; Mutation; Prevalence; Risk Assessment
PubMed: 18210922
DOI: No ID Found -
Interaction between the helicases genetically linked to Fanconi anemia group J and Bloom's syndrome.The EMBO Journal Feb 2011Bloom's syndrome (BS) and Fanconi anemia (FA) are autosomal recessive disorders characterized by cancer and chromosomal instability. BS and FA group J arise from...
Bloom's syndrome (BS) and Fanconi anemia (FA) are autosomal recessive disorders characterized by cancer and chromosomal instability. BS and FA group J arise from mutations in the BLM and FANCJ genes, respectively, which encode DNA helicases. In this work, FANCJ and BLM were found to interact physically and functionally in human cells and co-localize to nuclear foci in response to replication stress. The cellular level of BLM is strongly dependent upon FANCJ, and BLM is degraded by a proteasome-mediated pathway when FANCJ is depleted. FANCJ-deficient cells display increased sister chromatid exchange and sensitivity to replication stress. Expression of a FANCJ C-terminal fragment that interacts with BLM exerted a dominant negative effect on hydroxyurea resistance by interfering with the FANCJ-BLM interaction. FANCJ and BLM synergistically unwound a DNA duplex substrate with sugar phosphate backbone discontinuity, but not an 'undamaged' duplex. Collectively, the results suggest that FANCJ catalytic activity and its effect on BLM protein stability contribute to preservation of genomic stability and a normal response to replication stress.
Topics: Animals; Basic-Leucine Zipper Transcription Factors; Bloom Syndrome; Cell Nucleus; Cells, Cultured; DNA Helicases; DNA Replication; Fanconi Anemia; Fanconi Anemia Complementation Group Proteins; Genomic Instability; HeLa Cells; Humans; Insecta; Protein Binding; Protein Interaction Mapping; RecQ Helicases; Tissue Distribution
PubMed: 21240188
DOI: 10.1038/emboj.2010.362 -
The Journal of Cell Biology Apr 2001Bloom syndrome (BS) is an autosomal recessive disorder characterized by a high incidence of cancer and genomic instability. BLM, the protein defective in BS, is a...
Bloom syndrome (BS) is an autosomal recessive disorder characterized by a high incidence of cancer and genomic instability. BLM, the protein defective in BS, is a RecQ-like helicase, presumed to function in DNA replication, recombination, or repair. BLM localizes to promyelocytic leukemia protein (PML) nuclear bodies and is expressed during late S and G2. We show, in normal human cells, that the recombination/repair proteins hRAD51 and replication protein (RP)-A assembled with BLM into a fraction of PML bodies during late S/G2. Biochemical experiments suggested that BLM resides in a nuclear matrix-bound complex in which association with hRAD51 may be direct. DNA-damaging agents that cause double strand breaks and a G2 delay induced BLM by a p53- and ataxia-telangiectasia mutated independent mechanism. This induction depended on the G2 delay, because it failed to occur when G2 was prevented or bypassed. It coincided with the appearance of foci containing BLM, PML, hRAD51 and RP-A, which resembled ionizing radiation-induced foci. After radiation, foci containing BLM and PML formed at sites of single-stranded DNA and presumptive repair in normal cells, but not in cells with defective PML. Our findings suggest that BLM is part of a dynamic nuclear matrix-based complex that requires PML and functions during G2 in undamaged cells and recombinational repair after DNA damage.
Topics: Adenosine Triphosphatases; Bloom Syndrome; Blotting, Western; Cell Cycle; Cell Fractionation; Cell Nucleus; Cells, Cultured; DNA Damage; DNA Helicases; DNA Repair; DNA-Binding Proteins; Fibroblasts; Flow Cytometry; Humans; Microscopy, Fluorescence; Neoplasm Proteins; Nuclear Proteins; Promyelocytic Leukemia Protein; Proteins; Rad51 Recombinase; RecQ Helicases; Replication Protein A; Transcription Factors; Tubulin; Tumor Suppressor Proteins; X-Rays
PubMed: 11309417
DOI: 10.1083/jcb.153.2.367 -
Fly Oct 2017Drosophila melanogaster chromosome 4 is an anomaly because of its small size, chromatin structure, and most notably its lack of crossing over during meiosis. Earlier... (Review)
Review
Drosophila melanogaster chromosome 4 is an anomaly because of its small size, chromatin structure, and most notably its lack of crossing over during meiosis. Earlier ideas about the absence of crossovers on 4 hypothesize that these unique characteristics function to prevent crossovers. Here, we explore hypotheses about the absence of crossovers on 4, how these have been addressed, and new insights into the mechanism behind this suppression. We review recently published results that indicate that global crossover patterning, in particular the centromere effect, make a major contribution to the prevention of crossovers on 4.
Topics: Animals; Chromosomes, Insect; Crossing Over, Genetic; Drosophila Proteins; Drosophila melanogaster; Meiosis
PubMed: 28426351
DOI: 10.1080/19336934.2017.1321181 -
Frontiers in Bioscience (Landmark... Jan 2013Telomeres are nucleoprotein structures at the ends of linear chromosomes that protect them from being recognized as DNA double stranded breaks. Telomeres shorten with... (Review)
Review
Telomeres are nucleoprotein structures at the ends of linear chromosomes that protect them from being recognized as DNA double stranded breaks. Telomeres shorten with every cell division and in the absence of the checkpoint mechanisms critical telomere shortening leads to chromosome end fusions and genomic instability. Cancer cells achieve immortality by engaging in one of the two known mechanisms for telomere maintenance: elongation by telomerase or through recombination. Recombination based elongation of telomeres, also known as alternative lengthening of telomeres or ALT, is prevalent among cancers of mesenchymal origin. However, the conditions favoring ALT emergence are not known. Here we will discuss possible players in ALT mechanisms, including recruitment of telomeres to recombination centers, alterations of telomere associated proteins and modifications at the level of chromatin that could generate recombination permissive conditions at telomeres.
Topics: Animals; DNA Helicases; DNA Methylation; Exodeoxyribonucleases; Genomic Instability; Heterochromatin; Humans; Mice; RecQ Helicases; Recombination, Genetic; Shelterin Complex; Telomerase; Telomere; Telomere Homeostasis; Telomere Shortening; Telomere-Binding Proteins; Werner Syndrome Helicase
PubMed: 23276906
DOI: 10.2741/4084 -
The Journal of Biological Chemistry Sep 1993Ataxia telangiectasia (AT) and Bloom's syndrome (BS) patients are characterized by sensitivity to radiation, increased lymphoid malignancy, and frequent translocations...
Ataxia telangiectasia (AT) and Bloom's syndrome (BS) patients are characterized by sensitivity to radiation, increased lymphoid malignancy, and frequent translocations to the antigen receptor loci. Because of these features, there has been a persistent question as to whether the V(D)J recombinase might be abnormal in cells from these patients. Such abnormalities might be due to inappropriate to inaccurate expression of components of the V(D)J recombinase or due to mutation in a component shared between V(D)J recombination and other cellular processes, such as DNA repair. Bloom's syndrome is associated with a ligation deficiency, and this activity may contribute in the end resolution steps of both site-specific and general DNA-processing reactions. In the current study, we have activated V(D)J recombination in normal, AT, and BS fibroblasts and in fibroblasts from a patient with mutations that largely abolish DNA ligase I activity. We find that the signal and coding joint formation of the V(D)J recombination reaction are entirely normal in AT, BS, and DNA ligase I mutant cells. In addition to ruling out abnormalities of the V(D)J recombinase in AT, BS, and DNA ligase I mutant cells, these studies suggest that DNA ligase I is unlikely to be required for signal or coding end joining in the V(D)J recombination reaction.
Topics: Ataxia Telangiectasia; Base Sequence; Bloom Syndrome; Cell Line, Transformed; DNA; DNA Ligase ATP; DNA Ligases; DNA Nucleotidyltransferases; Fibroblasts; Gene Expression; Genes, RAG-1; Humans; Immunologic Deficiency Syndromes; Molecular Sequence Data; Mutagenesis; Recombination, Genetic; Simian virus 40; Substrate Specificity; Transfection; VDJ Recombinases
PubMed: 8397200
DOI: No ID Found -
Computational and Structural... 2022SMYD3 overexpression in several human cancers highlights its crucial role in carcinogenesis. Nonetheless, SMYD3 specific activity in cancer development and progression...
SMYD3 overexpression in several human cancers highlights its crucial role in carcinogenesis. Nonetheless, SMYD3 specific activity in cancer development and progression is currently under debate. Taking advantage of a library of rare tripeptides, which we first tested for their binding affinity to SMYD3 and then used as probes, we recently identified BRCA2, ATM, and CHK2 as direct SMYD3 interactors. To gain insight into novel SMYD3 cancer-related roles, here we performed a comprehensive analysis to cluster all potential SMYD3-interacting proteins identified by screening the human proteome for the previously tested tripeptides, based on their involvement in cancer hallmarks. Remarkably, we identified mTOR, BLM, MET, AMPK, and p130 as new SMYD3 interactors implicated in cancer processes. Further studies are needed to characterize the functional mechanisms underlying these interactions. Still, these findings could be useful to devise novel therapeutic strategies based on the combined inhibition of SMYD3 and its newly identified molecular partners. Of note, our methodology may be useful to search for unidentified interactors of other proteins of interest.
PubMed: 35495117
DOI: 10.1016/j.csbj.2022.03.037 -
Molecular Biology of the Cell Apr 2022Homology-directed repair of DNA double-strand breaks (DSBs) represents a highly faithful pathway. Non-crossover repair dominates in mitotically growing cells, likely...
Homology-directed repair of DNA double-strand breaks (DSBs) represents a highly faithful pathway. Non-crossover repair dominates in mitotically growing cells, likely through a preference for synthesis-dependent strand annealing (SDSA). How homology-directed repair mechanism choice is orchestrated in time and space is not well understood. Here, we develop a microscopy-based assay in living fission yeast to determine the dynamics and kinetics of an engineered, site-specific interhomologue repair event. We observe highly efficient homology search and homology-directed repair in this system. Surprisingly, the initial distance between the DSB and the donor sequence does not correlate with the duration of repair. Instead, we observe that repair often involves multiple site-specific and Rad51-dependent colocalization events between the DSB and donor sequence. Upon loss of the RecQ helicase Rqh1 (BLM in humans) we observe rapid repair possibly involving a single strand invasion event, suggesting that multiple strand invasion cycles antagonized by Rqh1 could reflect ongoing SDSA. However, failure to colocalize with the donor sequence and execute repair is also more likely in cells, possibly reflecting erroneous strand invasion. This work has implications for the molecular etiology of Bloom syndrome, caused by mutations in BLM and characterized by aberrant sister chromatid crossovers and inefficient repair.
Topics: DNA Breaks, Double-Stranded; DNA Helicases; DNA Repair; DNA Replication; Humans; Recombinational DNA Repair; Schizosaccharomyces; Schizosaccharomyces pombe Proteins
PubMed: 35080989
DOI: 10.1091/mbc.E20-07-0433 -
The Protein Journal Jan 2011The American Cancer Society's 2009 statistics estimate that 1 out of every 4 deaths is cancer related. Genomic instability is a common feature of cancerous states, and...
The American Cancer Society's 2009 statistics estimate that 1 out of every 4 deaths is cancer related. Genomic instability is a common feature of cancerous states, and an increase in genomic instability is the diagnostic feature of Bloom Syndrome. Bloom Syndrome, a rare disorder characterized by a predisposition to cancer, is caused by mutations of the BLM gene. This study focuses on the partnerships of BLM protein to RAD51, a Homologous Recombination repair protein essential for survival. A systematic set of BLM deletion fragments were generated to refine the protein binding domains of BLM to RAD51 and determine interacting regions of BLM and ssDNA. Results show that RAD51 and ssDNA interact in overlapping regions; BLM₁₀₀₋₂₁₄ and BLM₁₃₁₇₋₁₃₆₇. The overlapping nature of these regions suggests a preferential binding for one partner that could function to regulate homologous recombination and therefore helps to clarify the role of BLM in maintaining genomic stability.
Topics: Binding, Competitive; Bloom Syndrome; DNA Breaks, Double-Stranded; DNA Repair; DNA-Binding Proteins; Genomic Instability; Humans; Protein Interaction Domains and Motifs; Rad51 Recombinase; RecQ Helicases; Recombination, Genetic
PubMed: 21113733
DOI: 10.1007/s10930-010-9295-8 -
Molecular and Cellular Biology Feb 2004Bloom's syndrome (BS) is a human genetic disorder associated with cancer predisposition. The BS gene product, BLM, is a member of the RecQ helicase family, which is...
Bloom's syndrome (BS) is a human genetic disorder associated with cancer predisposition. The BS gene product, BLM, is a member of the RecQ helicase family, which is required for the maintenance of genome stability in all organisms. In budding and fission yeasts, loss of RecQ helicase function confers sensitivity to inhibitors of DNA replication, such as hydroxyurea (HU), by failure to execute normal cell cycle progression following recovery from such an S-phase arrest. We have examined the role of the human BLM protein in recovery from S-phase arrest mediated by HU and have probed whether the stress-activated ATR kinase, which functions in checkpoint signaling during S-phase arrest, plays a role in the regulation of BLM function. We show that, consistent with a role for BLM in protection of human cells against the toxicity associated with arrest of DNA replication, BS cells are hypersensitive to HU. BLM physically associates with ATR (ataxia telangiectasia and rad3(+) related) protein and is phosphorylated on two residues in the N-terminal domain, Thr-99 and Thr-122, by this kinase. Moreover, BS cells ectopically expressing a BLM protein containing phosphorylation-resistant T99A/T122A substitutions fail to adequately recover from an HU-induced replication blockade, and the cells subsequently arrest at a caffeine-sensitive G(2)/M checkpoint. These abnormalities are not associated with a failure of the BLM-T99A/T122A protein to localize to replication foci or to colocalize either with ATR itself or with other proteins that are required for response to DNA damage, such as phosphorylated histone H2AX and RAD51. Our data indicate that RecQ helicases play a conserved role in recovery from perturbations in DNA replication and are consistent with a model in which RecQ helicases act to restore productive DNA replication following S-phase arrest and hence prevent subsequent genomic instability.
Topics: Adenosine Triphosphatases; Antineoplastic Agents; Ataxia Telangiectasia Mutated Proteins; Bloom Syndrome; Cell Cycle Proteins; DNA Helicases; Fibroblasts; Genetic Predisposition to Disease; Humans; Hydroxyurea; Phosphorylation; Phosphotransferases; Protein Serine-Threonine Kinases; RecQ Helicases; S Phase; Threonine
PubMed: 14729972
DOI: 10.1128/MCB.24.3.1279-1291.2004