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The FEBS Journal Jul 2013The discovery of telomeres dates back to the early 20th century. In humans, telomeres are heterochromatic structures with tandem DNA repeats of 5'-TTAGGG-3' at the... (Review)
Review
The discovery of telomeres dates back to the early 20th century. In humans, telomeres are heterochromatic structures with tandem DNA repeats of 5'-TTAGGG-3' at the chromosomal ends. Telomere length varies greatly among species and ranges from 10 to 15 kb in humans. With each cell division, telomeres shorten progressively because of the 'end-replication problem'. Short or dysfunctional telomeres are often recognized as DNA DSBs, triggering cell-cycle arrest and result in cellular senescence or apoptotic cell death. Therefore, telomere shortening serves as an important tumor-suppressive mechanism by limiting cellular proliferative capacity by regulating senescence checkpoint activation. Although telomeres serve as a mitotic clock to cells, they also confer capping on chromosomes, with help from telomere-associated proteins. Over the past decades, many studies of telomere biology have demonstrated that telomeres and telomere-associated proteins are implicated in human genetic diseases. In addition, it has become more apparent that accelerated telomere erosion is associated with a myriad of metabolic and inflammatory diseases. Moreover, critically short or unprotected telomeres are likely to form telomeric fusions, leading to genomic instability, the cornerstone for carcinogenesis. In light of these, this minireview summarizes studies on telomeres and telomere-associated proteins in human diseases. Elucidating the roles of telomeres involved in the mechanisms underlying pathogenesis of these diseases may open up new possibilities for novel molecular targets as well as provide important diagnostic and therapeutic implications.
Topics: Anemia, Aplastic; Animals; DNA Repair-Deficiency Disorders; Dyskeratosis Congenita; Humans; Idiopathic Pulmonary Fibrosis; Metabolic Diseases; Neoplasms; Telomere Shortening
PubMed: 23647631
DOI: 10.1111/febs.12326 -
The Journal of Investigative... Aug 2009Progeroid syndromes are a group of diseases characterized by signs of premature aging. These syndromes comprise diseases such as Werner syndrome, Bloom syndrome,... (Review)
Review
Progeroid syndromes are a group of diseases characterized by signs of premature aging. These syndromes comprise diseases such as Werner syndrome, Bloom syndrome, Rothmund-Thomson syndrome, Hutchinson-Gilford syndrome, Fanconi anemia, and ataxia-telangiectasia, as well as xeroderma pigmentosum, trichothiodystrophy, and Cockayne syndrome. Clinical symptoms of premature aging are skin atrophy with loss of cutaneous elasticity, dysfunction of cutaneous appendices, degeneration of the central nervous system and an increased susceptibility for malignant tumors. Genetic defects in the repair of DNA damage can lead to progeroid syndromes, and it is becoming increasingly evident that direct DNA damage and indirect damage by highly reactive oxygen species play central roles in aging. The clinical signs of progeroid syndromes and the molecular aspects of UV (ultraviolet radiation)-induced oxidative stress in aging are discussed.Journal of Investigative Dermatology Symposium Proceedings (2009) 14, 8-14; doi:10.1038/jidsymp.2009.6.
Topics: Ataxia Telangiectasia; Bloom Syndrome; Cockayne Syndrome; DNA Damage; DNA Repair; Fanconi Anemia; Female; Humans; Male; Models, Biological; Oxidative Stress; Progeria; Rothmund-Thomson Syndrome; Trichothiodystrophy Syndromes; Ultraviolet Rays; Werner Syndrome; Xeroderma Pigmentosum
PubMed: 19675546
DOI: 10.1038/jidsymp.2009.6 -
Clinical Cancer Research : An Official... Jun 2017DNA repair syndromes are heterogeneous disorders caused by pathogenic variants in genes encoding proteins key in DNA replication and/or the cellular response to DNA... (Review)
Review
DNA repair syndromes are heterogeneous disorders caused by pathogenic variants in genes encoding proteins key in DNA replication and/or the cellular response to DNA damage. The majority of these syndromes are inherited in an autosomal-recessive manner, but autosomal-dominant and X-linked recessive disorders also exist. The clinical features of patients with DNA repair syndromes are highly varied and dependent on the underlying genetic cause. Notably, all patients have elevated risks of syndrome-associated cancers, and many of these cancers present in childhood. Although it is clear that the risk of cancer is increased, there are limited data defining the true incidence of cancer and almost no evidence-based approaches to cancer surveillance in patients with DNA repair disorders. This article is the product of the October 2016 AACR Childhood Cancer Predisposition Workshop, which brought together experts from around the world to discuss and develop cancer surveillance guidelines for children with cancer-prone disorders. Herein, we focus on the more common of the rare DNA repair disorders: ataxia telangiectasia, Bloom syndrome, Fanconi anemia, dyskeratosis congenita, Nijmegen breakage syndrome, Rothmund-Thomson syndrome, and Xeroderma pigmentosum. Dedicated syndrome registries and a combination of basic science and clinical research have led to important insights into the underlying biology of these disorders. Given the rarity of these disorders, it is recommended that centralized centers of excellence be involved directly or through consultation in caring for patients with heritable DNA repair syndromes.
Topics: Ataxia Telangiectasia; Bloom Syndrome; Child; DNA Repair; DNA Repair-Deficiency Disorders; Early Detection of Cancer; Fanconi Anemia; Humans; Neoplasms; Xeroderma Pigmentosum
PubMed: 28572264
DOI: 10.1158/1078-0432.CCR-17-0465 -
Molecular Syndromology Jun 2020Bloom syndrome is an autosomal recessive disorder characterized by prenatal and postnatal growth deficiency, photosensitive skin changes, immune deficiency, insulin...
Bloom syndrome is an autosomal recessive disorder characterized by prenatal and postnatal growth deficiency, photosensitive skin changes, immune deficiency, insulin resistance, and a greatly increased risk of early-onset cancer and development of multiple malignancies. Loss-of-function variants of the gene, which codes for a RecQ helicase, cause Bloom syndrome. We report a consanguineous family, with 2 siblings showing clinical signs of suspected chromosome breakage disorder. One of them developed recurrent malignant lymphoma during lifetime. We performed next-generation sequencing analysis, focusing on cancer predisposition syndromes. We identified a homozygous pathogenic nonsense variant c.1642C>T (p.Gln548*) in the gene in the proband, associated with Bloom syndrome. Sanger sequencing validated the presence of a homozygous pathogenic variant in the proband and also in the brother with short stature. In this article, we will focus on the clinical presentation of the syndrome in this particular family as well as the characteristics of malignancies found in the proband.
PubMed: 32655338
DOI: 10.1159/000507006 -
The Israel Medical Association Journal... Feb 2002The Bloom syndrome gene, BLM, was mapped to 15q26.1 and its product was found to encode a RecQ DNA helicase. The Fanconi's anemia complementation group C gene was mapped...
BACKGROUND
The Bloom syndrome gene, BLM, was mapped to 15q26.1 and its product was found to encode a RecQ DNA helicase. The Fanconi's anemia complementation group C gene was mapped to chromosome 9q22.3, but its product function is not sufficiently clear. Both are recessive disorders associated with an elevated predisposition to cancer due to genomic instability. A single predominant mutation of each disorder was reported in Ashkenazi Jews: 2281delATCTGAinsTAGATTC for Bloom syndrome (BLM-ASH) and IVS4 + 4AT for Fanconi's anemia complementation group C.
OBJECTIVES
To provide additional verification of the mutation rate of BLM and FACC in unselected Ashkenazi and non-Ashkenazi populations analyzed at the Sheba Medical Center, and to trace the origin of each mutation.
METHODS
We used polymerase chain reaction to identify mutations of the relevant genomic fragments, restriction analysis and gel electrophoresis. We then applied the Pronto kit to verify the results in 244 samples and there was an excellent match.
RESULTS
A heterozygote frequency of 1:111 for BLM-ASH and 1:92 for FACC was detected in more than 4,000 participants, none of whom reported a family history of the disorders. The Pronto kit confirmed all heterozygotes. Neither of the mutations was detected in 950 anonymous non-Ashkenazi Jews. The distribution pattern of parental origin differed significantly between the two carrier groups, as well as between each one and the general population.
CONCLUSIONS
These findings as well as the absence of the mutations in non-Ashkenazi Jews suggest that: a) the mutations originated in the Israelite population that was exiled from Palestine by the Roman Empire in 70 AD and settled in Europe (Ashkenazi), in contrast to those who remained; and b) the difference in origin distribution of the BS and FACC mutations can be explained by either a secondary migration of a subgroup with a subsequent genetic drift, or a separate geographic region of introduction for each mutation.
Topics: Bloom Syndrome; Electrophoresis, Agar Gel; Fanconi Anemia; Female; Gene Frequency; Genetic Testing; Heterozygote; Humans; Israel; Jews; Male; Mutation; Polymerase Chain Reaction; Restriction Mapping
PubMed: 11876000
DOI: No ID Found -
PLoS Genetics Dec 2016Bloom syndrome is a recessive human genetic disorder with features of genome instability, growth deficiency and predisposition to cancer. The only known causative gene...
Bloom syndrome is a recessive human genetic disorder with features of genome instability, growth deficiency and predisposition to cancer. The only known causative gene is the BLM helicase that is a member of a protein complex along with topoisomerase III alpha, RMI1 and 2, which maintains replication fork stability and dissolves double Holliday junctions to prevent genome instability. Here we report the identification of a second gene, RMI2, that is deleted in affected siblings with Bloom-like features. Cells from homozygous individuals exhibit elevated rates of sister chromatid exchange, anaphase DNA bridges and micronuclei. Similar genome and chromosome instability phenotypes are observed in independently derived RMI2 knockout cells. In both patient and knockout cell lines reduced localisation of BLM to ultra fine DNA bridges and FANCD2 at foci linking bridges are observed. Overall, loss of RMI2 produces a partially active BLM complex with mild features of Bloom syndrome.
Topics: Bloom Syndrome; Chromosomal Instability; DNA Helicases; DNA, Cruciform; DNA-Binding Proteins; Fanconi Anemia Complementation Group D2 Protein; Genetic Predisposition to Disease; Genomic Instability; Humans; Multiprotein Complexes; Neoplasms; Nuclear Proteins; Sister Chromatid Exchange
PubMed: 27977684
DOI: 10.1371/journal.pgen.1006483 -
Cytogenetic and Genome Research 2014Biallelic mutations in BLM cause Bloom syndrome (BS), a genome instability disorder characterized by growth retardation, sun sensitivity and a predisposition to cancer....
Biallelic mutations in BLM cause Bloom syndrome (BS), a genome instability disorder characterized by growth retardation, sun sensitivity and a predisposition to cancer. As evidence of decreased genome stability, BS cells demonstrate not only elevated levels of spontaneous sister chromatid exchanges (SCEs), but also exhibit chromosomal radial formation. The molecular nature and mechanism of radial formation is not known, but radials have been thought to be DNA recombination intermediates between homologs that failed to resolve. However, we find that radials in BS cells occur over 95% between non-homologous chromosomes, and occur non-randomly throughout the genome. BLM must be phosphorylated at T99 and T122 for certain cell cycle checkpoints, but it is not known whether these modifications are necessary to suppress radial formation. We find that exogenous BLM constructs preventing phosphorylation at T99 and T122 are not able to suppress radial formation in BS cells, but are able to inhibit SCE formation. These findings indicate that BLM functions in 2 distinct pathways requiring different modifications. In one pathway, for which the phosphorylation marks appear dispensable, BLM functions to suppress SCE formation. In a second pathway, T99 and T122 phosphorylations are essential for suppression of chromosomal radial formation, both those formed spontaneously and those formed following interstrand crosslink damage.
Topics: Bloom Syndrome; Cells, Cultured; Chromosomal Instability; Chromosomes, Human; Humans; Monte Carlo Method; Mutation; Phosphorylation; RecQ Helicases; Sister Chromatid Exchange
PubMed: 25766002
DOI: 10.1159/000375247 -
Biochimie Aug 2011The physiological and pharmacological role of nucleic acids structures folded into the non canonical G-quadruplex conformation have recently emerged. Their activities... (Review)
Review
The physiological and pharmacological role of nucleic acids structures folded into the non canonical G-quadruplex conformation have recently emerged. Their activities are targeted at vital cellular processes including telomere maintenance, regulation of transcription and processing of the pre-messenger or telomeric RNA. In addition, severe conditions like cancer, fragile X syndrome, Bloom syndrome, Werner syndrome and Fanconi anemia J are related to genomic defects that involve G-quadruplex forming sequences. In this connection G-quadruplex recognition and processing by nucleic acid directed proteins and enzymes represents a key event to activate or deactivate physiological or pathological pathways. In this review we examine protein-G-quadruplex recognition in physiologically significant conditions and discuss how to possibly exploit the interactions' selectivity for targeted therapeutic intervention.
Topics: Antibodies; Aptamers, Nucleotide; Base Sequence; DNA Helicases; Drug Design; G-Quadruplexes; Heterogeneous-Nuclear Ribonucleoproteins; Molecular Sequence Data; Peptides; Promoter Regions, Genetic; Protein Biosynthesis; Proteins; RNA Helicases; RNA, Untranslated; Shelterin Complex; Telomere; Telomere-Binding Proteins; Transcription, Genetic
PubMed: 21549174
DOI: 10.1016/j.biochi.2011.04.018 -
Methods (San Diego, Calif.) May 2009The use of co-immunoprecipitation (co-IP) to purify multi-protein complexes has contributed greatly to our understanding of the DNA damage response network associated... (Review)
Review
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.
Topics: Bloom Syndrome; Carrier Proteins; DNA Damage; DNA Topoisomerases, Type I; DNA-Binding Proteins; Fanconi Anemia; Humans; Nuclear Proteins; RecQ Helicases
PubMed: 19245838
DOI: 10.1016/j.ymeth.2009.02.011 -
Frontiers in Genetics 2014The RecQ family DNA helicases Werner syndrome protein (WRN) and Bloom syndrome protein (BLM) play a key role in protecting the genome against deleterious changes. In... (Review)
Review
The RecQ family DNA helicases Werner syndrome protein (WRN) and Bloom syndrome protein (BLM) play a key role in protecting the genome against deleterious changes. In humans, mutations in these proteins lead to rare genetic diseases associated with cancer predisposition and accelerated aging. WRN and BLM are distinguished from other helicases by possessing signature tandem domains toward the C terminus, referred to as the RecQ C-terminal (RQC) and helicase-and-ribonuclease D-C-terminal (HRDC) domains. Although the precise function of the HRDC domain remains unclear, the previous crystal structure of a WRN RQC-DNA complex visualized a central role for the RQC domain in recognizing, binding and unwinding DNA at branch points. In particular, a prominent hairpin structure (the β-wing) within the RQC winged-helix motif acts as a scalpel to induce the unpairing of a Watson-Crick base pair at the DNA duplex terminus. A similar RQC-DNA interaction was also observed in the recent crystal structure of a BLM-DNA complex. I review the latest structures of WRN and BLM, and then provide a docking simulation of BLM with a Holliday junction. The model offers an explanation for the efficient branch migration activity of the RecQ family toward recombination and repair intermediates.
PubMed: 25400656
DOI: 10.3389/fgene.2014.00366