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Familial Cancer Jan 2022Bloom syndrome (BS) is a genomic and chromosomal instability disorder with prodigious cancer predisposition caused by pathogenic variants in BLM. We report the clinical...
Bloom syndrome (BS) is a genomic and chromosomal instability disorder with prodigious cancer predisposition caused by pathogenic variants in BLM. We report the clinical and genetic details of a boy who first presented with infantile fibrosarcoma (IFS) at the age of 6 months and subsequently was diagnosed with BS at the age of 9 years. Molecular analysis identified the pathogenic germline BLM sequence variants (c.1642C>T and c.2207_2212delinsTAGATTC). This is the first report of IFS related to BS, for which we show that both BLM alleles are maintained in the tumor and demonstrate a TPM3-NTKR1 fusion transcript in the IFS. Our communication emphasizes the importance of long-term follow up after treatment for pediatric neoplastic conditions, as clues to important genetic entities might manifest later, and the identification of a heritable tumor predisposition often leads to changes in patient surveillance and management.
Topics: Alleles; Bloom Syndrome; Child; Fibrosarcoma; Genetic Predisposition to Disease; Genotype; Humans; Infant; Male; RecQ Helicases; Tropomyosin
PubMed: 33219493
DOI: 10.1007/s10689-020-00221-1 -
Molecular and Cellular Biology Oct 2004The Werner and Bloom syndromes are caused by loss-of-function mutations in WRN and BLM, respectively, which encode the RecQ family DNA helicases WRN and BLM,...
The Werner and Bloom syndromes are caused by loss-of-function mutations in WRN and BLM, respectively, which encode the RecQ family DNA helicases WRN and BLM, respectively. Persons with Werner syndrome displays premature aging of the skin, vasculature, reproductive system, and bone, and those with Bloom syndrome display more limited features of aging, including premature menopause; both syndromes involve genome instability and increased cancer. The proteins participate in recombinational repair of stalled replication forks or DNA breaks, but the precise functions of the proteins that prevent rapid aging are unknown. Accumulating evidence points to telomeres as targets of WRN and BLM, but the importance in vivo of the proteins in telomere biology has not been tested. We show that Wrn and Blm mutations each accentuate pathology in later-generation mice lacking the telomerase RNA template Terc, including acceleration of phenotypes characteristic of latest-generation Terc mutants. Furthermore, pathology not observed in Terc mutants but similar to that observed in Werner syndrome and Bloom syndrome, such as bone loss, was observed. The pathology was accompanied by enhanced telomere dysfunction, including end-to-end chromosome fusions and greater loss of telomere repeat DNA compared with Terc mutants. These findings indicate that telomere dysfunction may contribute to the pathogenesis of Werner syndrome and Bloom syndrome.
Topics: Animals; Bloom Syndrome; Body Constitution; Infertility; Intestine, Small; Longevity; Male; Mice; Mutation; RNA; Telomerase; Telomere; Testis; Werner Syndrome; Wound Healing
PubMed: 15367665
DOI: 10.1128/MCB.24.19.8437-8446.2004 -
Annual Review of Biochemistry 2014RecQ helicases are an important family of genome surveillance proteins conserved from bacteria to humans. Each of the five human RecQ helicases plays critical roles in... (Review)
Review
RecQ helicases are an important family of genome surveillance proteins conserved from bacteria to humans. Each of the five human RecQ helicases plays critical roles in genome maintenance and stability, and the RecQ protein family members are often referred to as guardians of the genome. The importance of these proteins in cellular homeostasis is underscored by the fact that defects in BLM, WRN, and RECQL4 are linked to distinct heritable human disease syndromes. Each human RecQ helicase has a unique set of protein-interacting partners, and these interactions dictate its specialized functions in genome maintenance, including DNA repair, recombination, replication, and transcription. Human RecQ helicases also interact with each other, and these interactions have significant impact on enzyme function. Future research goals in this field include a better understanding of the division of labor among the human RecQ helicases and learning how human RecQ helicases collaborate and cooperate to enhance genome stability.
Topics: DNA; DNA Repair; DNA Replication; Exodeoxyribonucleases; Genome, Human; Genomic Instability; Humans; Models, Molecular; Molecular Conformation; Multigene Family; Protein Processing, Post-Translational; Protein Structure, Tertiary; RecQ Helicases; Recombination, Genetic; S Phase; Werner Syndrome Helicase
PubMed: 24606147
DOI: 10.1146/annurev-biochem-060713-035428 -
American Journal of Human Genetics Aug 2018Bloom syndrome, caused by biallelic mutations in BLM, is characterized by prenatal-onset growth deficiency, short stature, an erythematous photosensitive malar rash, and...
Bloom syndrome, caused by biallelic mutations in BLM, is characterized by prenatal-onset growth deficiency, short stature, an erythematous photosensitive malar rash, and increased cancer predisposition. Diagnostically, a hallmark feature is the presence of increased sister chromatid exchanges (SCEs) on cytogenetic testing. Here, we describe biallelic mutations in TOP3A in ten individuals with prenatal-onset growth restriction and microcephaly. TOP3A encodes topoisomerase III alpha (TopIIIα), which binds to BLM as part of the BTRR complex, and promotes dissolution of double Holliday junctions arising during homologous recombination. We also identify a homozygous truncating variant in RMI1, which encodes another component of the BTRR complex, in two individuals with microcephalic dwarfism. The TOP3A mutations substantially reduce cellular levels of TopIIIα, and consequently subjects' cells demonstrate elevated rates of SCE. Unresolved DNA recombination and/or replication intermediates persist into mitosis, leading to chromosome segregation defects and genome instability that most likely explain the growth restriction seen in these subjects and in Bloom syndrome. Clinical features of mitochondrial dysfunction are evident in several individuals with biallelic TOP3A mutations, consistent with the recently reported additional function of TopIIIα in mitochondrial DNA decatenation. In summary, our findings establish TOP3A mutations as an additional cause of prenatal-onset short stature with increased cytogenetic SCEs and implicate the decatenation activity of the BTRR complex in their pathogenesis.
PubMed: 30057030
DOI: 10.1016/j.ajhg.2018.07.001 -
Nucleic Acids Research Jul 2001BLM and WRN, the products of the Bloom's and Werner's syndrome genes, are members of the RecQ family of DNA helicases. Although both have been shown previously to unwind...
BLM and WRN, the products of the Bloom's and Werner's syndrome genes, are members of the RecQ family of DNA helicases. Although both have been shown previously to unwind simple, partial duplex DNA substrates with 3'-->5' polarity, little is known about the structural features of DNA that determine the substrate specificities of these enzymes. We have compared the substrate specificities of the BLM and WRN proteins using a variety of partial duplex DNA molecules, which are based upon a common core nucleotide sequence. We show that neither BLM nor WRN is capable of unwinding duplex DNA from a blunt-ended terminus or from an internal nick. However, both enzymes efficiently unwind the same blunt-ended duplex containing a centrally located 12 nt single-stranded 'bubble', as well as a synthetic X-structure (a model for the Holliday junction recombination intermediate) in which each 'arm' of the 4-way junction is blunt-ended. Surprisingly, a 3'-tailed duplex, a standard substrate for 3'-->5' helicases, is unwound much less efficiently by BLM and WRN than are the bubble and X-structure substrates. These data show conclusively that a single-stranded 3'-tail is not a structural requirement for unwinding of standard B-form DNA by these helicases. BLM and WRN also both unwind a variety of different forms of G-quadruplex DNA, a structure that can form at guanine-rich sequences present at several genomic loci. Our data indicate that BLM and WRN are atypical helicases that are highly DNA structure specific and have similar substrate specificities. We interpret these data in the light of the genomic instability and hyper-recombination characteristics of cells from individuals with Bloom's or Werner's syndrome.
Topics: Base Sequence; Bloom Syndrome; Crossing Over, Genetic; DNA; DNA Helicases; Humans; Nucleic Acid Conformation; Oligodeoxyribonucleotides; Substrate Specificity; Werner Syndrome
PubMed: 11433031
DOI: 10.1093/nar/29.13.2843 -
Nucleic Acids Research 2006DNA helicases are required for virtually every aspect of DNA metabolism, including replication, repair, recombination and transcription. A comprehensive description of... (Review)
Review
DNA helicases are required for virtually every aspect of DNA metabolism, including replication, repair, recombination and transcription. A comprehensive description of these essential biochemical processes requires detailed understanding of helicase mechanisms. These enzymes are ubiquitous, having been identified in viruses, prokaryotes and eukaryotes. Disease states, such as xeroderma pigmentosum, Cockayne's syndrome, Bloom's syndrome and Werner's syndrome, have been linked to defects in specific genes coding for DNA helicases. Helicases have been placed into different subfamilies based on sequence comparison. The largest subgroups are termed superfamily 1 and superfamily 2. A proposed mechanism for helicases in these classes has been described in terms of an 'inchworm model'. The inchworm model includes conformational changes driven by ATP binding and hydrolysis that allow unidirectional translocation along DNA. A monomeric form of the enzyme is proposed to have two DNA-binding sites that enable sequential steps of DNA binding and release. Significant differences exist between helicases in important aspects of the models such as the oligomerization state of the enzyme with some helicases functioning as monomers, some as dimers and others as higher-order oligomers.
Topics: Bloom Syndrome; Cockayne Syndrome; DNA; DNA Helicases; DNA Replication; DNA-Binding Proteins; Eukaryotic Cells; Humans; Models, Biological; Recombination, Genetic; Werner Syndrome
PubMed: 16935880
DOI: 10.1093/nar/gkl501 -
Structure (London, England : 1993) Oct 2017Topoisomerase IIβ binding protein 1 (TopBP1) is a critical protein-protein interaction hub in DNA replication checkpoint control. It was proposed that TopBP1 BRCT5...
Topoisomerase IIβ binding protein 1 (TopBP1) is a critical protein-protein interaction hub in DNA replication checkpoint control. It was proposed that TopBP1 BRCT5 interacts with Bloom syndrome helicase (BLM) to regulate genome stability through either phospho-Ser304 or phospho-Ser338 of BLM. Here we show that TopBP1 BRCT5 specifically interacts with the BLM region surrounding pSer304, not pSer338. Our crystal structure of TopBP1 BRCT4/5 bound to BLM reveals recognition of pSer304 by a conserved pSer-binding pocket, and interactions between an FVPP motif N-terminal to pSer304 and a hydrophobic groove on BRCT5. This interaction utilizes the same surface of BRCT5 that recognizes the DNA damage mediator, MDC1; however the binding orientations of MDC1 and BLM are reversed. While the MDC1 interactions are largely electrostatic, the interaction with BLM has higher affinity and relies on a mix of electrostatics and hydrophobicity. We suggest that similar evolutionarily conserved interactions may govern interactions between TopBP1 and 53BP1.
Topics: Animals; Binding Sites; Carrier Proteins; Crystallography, X-Ray; DNA-Binding Proteins; Humans; Mice; Models, Molecular; Nuclear Proteins; Phosphorylation; Protein Conformation; RecQ Helicases; Serine; Trans-Activators
PubMed: 28919440
DOI: 10.1016/j.str.2017.08.005 -
Proceedings of the National Academy of... Nov 2012Bloom 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....
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.
Topics: Alleles; Amino Acid Sequence; Amino Acids; Bloom Syndrome; Diploidy; Heterozygote; Homozygote; Humans; Hydroxyurea; Molecular Sequence Data; Mutant Proteins; Mutation; Mutation, Missense; RecQ Helicases; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 23129629
DOI: 10.1073/pnas.1210304109 -
Archives of Disease in Childhood Feb 1998
Review
Topics: Ataxia Telangiectasia; Bloom Syndrome; Cockayne Syndrome; DNA Damage; DNA Repair; Fanconi Anemia; Hair; Humans; Infant, Newborn; Phenotype; Xeroderma Pigmentosum
PubMed: 9579166
DOI: 10.1136/adc.78.2.178 -
G3 (Bethesda, Md.) Apr 2022Genes on the long arm of the Drosophila melanogaster 4th chromosome are difficult to study because the chromosome lacks mitotic and meiotic recombination. Without...
Genes on the long arm of the Drosophila melanogaster 4th chromosome are difficult to study because the chromosome lacks mitotic and meiotic recombination. Without recombination numerous standard methods of genetic analysis are impossible. Here, we report new resources for the 4th. For mitotic recombination, we generated a chromosome with an FRT very near the centromere in 101F and a derivative that carries FRT101F with a distal ubiquitously expressed GAL80 transgene. This pair of chromosomes enables both unmarked and MARCM clones. For meiotic recombination, we demonstrate that a Bloom syndrome helicase and recombination defective double mutant genotype can create recombinant 4th chromosomes via female meiosis. All strains will be available to the community via the Bloomington Drosophila Stock Center. Additional resources for studies of the 4th are in preparation and will also be made available. The goal of the 4th Chromosome Resource Project is to accelerate the genetic analysis of protein-coding genes on the 4th, including the 44 genes with no demonstrated function. Studies of these previously inaccessible but largely conserved genes will close longstanding gaps in our knowledge of metazoan development and physiology.
Topics: Animals; Bloom Syndrome; Chromosomes; Clone Cells; Drosophila; Drosophila melanogaster; Female; Meiosis
PubMed: 35084488
DOI: 10.1093/g3journal/jkac019