GM08505

GM08505 Fibroblast from Skin, Unspecified

Description:

BLOOM SYNDROME; BLM
RECQ PROTEIN-LIKE 3; RECQL3

Affected:

Yes

Sex:

Female

Age:

27 YR (At Sampling)

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Heritable Diseases
Hereditary Cancers

Class

Repair Defective and Chromosomal Instability Syndromes

Biopsy Source

Unspecified

Cell Type

Fibroblast

Tissue Type

Skin

Transformant

Simian Virus 40

Sample Source

Fibroblast from Skin, Unspecified

Race

White

Ethnicity

ASHKENAZI

Family Member

Relation to Proband

proband

Confirmation

Clinical summary/Case history

Species

Homo sapiens

Common Name

Human

Remarks

Clinically affected; short stature; microcephaly; triangular, elongated facies; mild micrognathia; adenocarcinoma of colon; subserous myoma of uterus; hypoplastic, anovulatory ovaries; increased sister chromatid exchange; reduced DNA ligase I activity; near tetraploid line: counts range from 85 to 102 chromosomes per cell; karyotype is abnormal with multiple breaks and rearrangements; donor subject is homozygous for a 6-bp deletion/7-bp insertion [6-bp del/7-bp ins] at nucleotide 2,281 of the open reading frame of the RECQL3 gene, which results in a frameshift and a stop codon; this mutation was found in the fibroblast culture from this same donor (AG06040); B.S. Registry #42; SV40 transformed AG06040.

Characterizations

IDENTIFICATION OF SPECIES OF ORIGIN

Species of Origin Confirmed by Nucleoside Phosphorylase, Glucose-6-Phosphate Dehydrogenase, and Lactate Dehydrogenase Isoenzyme Electrophoresis and by Chromosome Analysis

DNASE ACTIVITY

Mezzina et al (Nucleic Acids Res 17:3091-3106,1989) studied DNase activity in this Bloom's syndrome culture. The results presented indicated that the DNase specific activity in crude extracts of this culture was higher than in appropriate control cell cultures.

DNA LIGASE I AND II

Willis et al. (Proc Natl Acad Sci USA 84:8016,1987) reported reduced DNA ligase I and normal DNA ligase II activity in fibroblasts. The DNA ligase I activity is more heat labile than normal. Lehmann et al (Cancer Res 48:6343-6347,1988) observed that this culture showed normal sensitivity to cell killing by dimethyl sulfate at low doses but showed greater sensitivity than normal cells at higher doses. These authors also reported that DNA ligase activity profiles for size fractionated cell-free extracts showed reduced DNA ligase I activity and normal DNA ligase II activity. Mezzina et al (Nucleic Acids Res 17:3091-3106,1989) studied DNA ligase activity in this Bloom's syndrome culture. The results presented indicated that the DNA ligase specific activity in crude extracts of this culture was higher than in control cells and that the ligase activity correlated to a major 130 kDa polypeptide.

MEX PHENOTYPES

Willis et al. (Proc Natl Acad Sci USA 84:8016,1987) reported a Mex+ phenotype based upon DNA (guanine-O6)-methyltransferase assay.

SISTER CHROMATID EXCHANGE ANALYSIS

High number of SCEs (60-80 per cell) in transformed fibroblast culture (Willis et al. Proc Natl Acad Sci USA 84:8016-8020,1987).

Gene

RECQL3

Chromosomal Location

15q26.1

Allelic Variant 1

604610.0001; BLOOM SYNDROME

Identified Mutation

6-BP DEL/7-BP INS; In 4 ostensibly unrelated persons of Jewish ancestry, Ellis et al. [Cell 83: 655 (1995)] found homozygosity for a 6-bp deletion/7-bp insertion at nucleotide 2281 of the BLM cDNA. Deletion of ATCTGA and insertion of TAGATTC caused the insertion of the novel codons for LDSR after amino acid 736, and after these codons there was a stop codon. Ellis et al. [Cell 83: 655 (1995)] concluded that a person carrying this deletion/insertion mutation was a founder of the Ashkenazi-Jewish population, and that nearly all Ashkenazi Jews with Bloom syndrome inherited the mutation identical by descent from this common ancestor.

Gene

RECQL3

Chromosomal Location

15q26.1

Allelic Variant 2

604610.0001; BLOOM SYNDROME

Identified Mutation

Phenotypic Data

Remarks

Publications

Zita Gál, Stavroula Boukoura, Kezia Catharina Oxe, Sara Badawi, Blanca Nieto, Lea Milling Korsholm, Sille Blangstrup Geisler, Ekaterina Dulina, Anna Vestergaard Rasmussen, Christina Dahl, Wei Lv, Huixin Xu, Xiaoguang Pan, Stefanos Arampatzis, Danai-Eleni Stratou, Panagiotis Galanos, Lin Lin, Per Guldberg, Jiri Bartek, Yonglun Luo & Dorthe H. Larsen, Hyper-recombination in ribosomal DNA is driven by long-range resection-independent RAD51 accumulation Nature Communications: 2024

PubMed ID: 39242676

Mazouzi A, Moser SC, Abascal F, van den Broek B, Del Castillo Velasco-Herrera M, van der Heijden I, Hekkelman M, Drenth AP, van der Burg E, Kroese LJ, Jalink K, Adams DJ, Jonkers J, Brummelkamp TR, FIRRM/C1orf112 mediates resolution of homologous recombination intermediates in response to DNA interstrand crosslinks Science advances9:eadf4409 2023

PubMed ID: 37256941

Silveira SC, Buhagiar-Labarchède G, Onclercq-Delic R, Gemble S, Bou Samra E, Mameri H, Duchambon P, Machon C, Guitton J, Amor-Guéret M, A decrease in NAMPT activity impairs basal PARP-1 activity in cytidine deaminase deficient-cells, independently of NAD Scientific reports10:13907 2020

PubMed ID: 32807821

Subramanian V, Rodemoyer B, Shastri V, Rasmussen LJ, Desler C, Schmidt KH, Bloom syndrome DNA helicase deficiency is associated with oxidative stress and mitochondrial network changes Scientific reports11:2157 2020

PubMed ID: 33495511

Gratia M, Rodero MP, Conrad C, Bou Samra E, Maurin M, Rice GI, Duffy D, Revy P, Petit F, Dale RC, Crow YJ, Amor-Gueret M, Manel N, Bloom syndrome protein restrains innate immune sensing of micronuclei by cGAS The Journal of experimental medicine216:1199-1213 2018

PubMed ID: 30936263

Behnfeldt JH, Acharya S, Tangeman L, Gocha AS, Keirsey J, Groden J, A tri-serine cluster within the topoisomerase IIa-interaction domain of the BLM helicase is required for regulating chromosome breakage in human cells Human molecular genetics216:1199-1213 2017

PubMed ID: 29385443

Killen MW, Stults DM, Wilson WA, Pierce AJ, Escherichia coli RecG functionally suppresses human Bloom syndrome phenotypes BMC molecular biology13:33 2012

PubMed ID: 23110454

Popuri V, Ramamoorthy M, Tadokoro T, Singh DK, Karmakar P, Croteau DL, Bohr VA, Recruitment and retention dynamics of RECQL5 at DNA double strand break sites DNA repair11:624-35 2012

PubMed ID: 22633600

Singh DK, Popuri V, Kulikowicz T, Shevelev I, Ghosh AK, Ramamoorthy M, Rossi ML, Janscak P, Croteau DL, Bohr VA, The human RecQ helicases BLM and RECQL4 cooperate to preserve genome stability Nucleic acids research40:6632-48 2012

PubMed ID: 22544709

Larocque JR, Jasin M, Mechanisms of recombination between diverged sequences in wild-type and BLM-deficient mouse and human cells Molecular and cellular biology30:1887-97 2010

PubMed ID: 20154148

Bhattacharyya S, Keirsey J, Russell B, Kavecansky J, Lillard-Wetherell K, Tahmaseb K, Turchi JJ, Groden J, Telomerase associated protein 1, HSP90 and topoisomerase IIalpha associate directly with the BLM helicase in immortalized cells using altand modulate its helicase activity using telomeric DNA substrates The Journal of biological chemistry30:1887-97 2009

PubMed ID: 19329795

Eladad S, Ye TZ, Hu P, Leversha M, Beresten S, Matunis MJ, Ellis NA, Intra-nuclear trafficking of the BLM helicase to DNA damage-induced foci is regulated by SUMO modification Human molecular genetics14:1351-65 2005

PubMed ID: 15829507

Yin J, Sobeck A, Xu C, Meetei AR, Hoatlin M, Li L, Wang W, BLAP75, an essential component of Bloom's syndrome protein complexes that maintain genome integrity. EMBO J24(7):1465-76 2005

PubMed ID: 15775963

Lillard-Wetherell K, Machwe A, Langland GT, Combs KA, Behbehani GK, Schonberg SA, German J, Turchi JJ, Orren DK, Groden J, Association and regulation of the BLM helicase by the telomere proteins TRF1 and TRF2 Hum Mol Genet13(17):1919-32 2004

PubMed ID: 15229185

Sharma S, Sommers JA, Wu L, Bohr VA, Hickson ID, Brosh RM Jr, Stimulation of flap endonuclease-1 by the Bloom's syndrome protein. J Biol Chem279(11):9847-56 2004

PubMed ID: 14688284

Gao H, Chen XB, McGowan CH, Mus81 endonuclease localizes to nucleoli and to regions of DNA damage in human S-phase cells. Mol Biol Cell14(12):4826-34 2003

PubMed ID: 14638871

Jack R. Edelman and Yue J. Lin, Accretion of unstable heterochromatin as the origin of double minute chromosomes: evidence from Bloom Syndrome Cytologia (Tokyo)68:75-82 2003

PubMed ID: 14638871

Ju R, Muller MT, Histone deacetylase inhibitors activate p21(WAF1) expression via ATM. Cancer Res63(11):2891-7 2003

PubMed ID: 12782595

Mandola MV, Stoehlmacher J, Muller-Weeks S, Cesarone G, Yu MC, Lenz HJ, Ladner RD, A novel single nucleotide polymorphism within the 5' tandem repeat polymorphism of the thymidylate synthase gene abolishes USF-1 binding and alters transcriptional activity. Cancer Res63(11):2898-904 2003

PubMed ID: 12782596

Traverso G, Bettegowda C, Kraus J, Speicher MR, Kinzler KW, Vogelstein B, Lengauer C, Hyper-recombination and genetic instability in BLM-deficient epithelial cells. Cancer Res63(24):8578-81 2003

PubMed ID: 14695165

Langland G, Elliott J, Li Y, Creaney J, Dixon K, Groden J, The BLM helicase is necessary for normal DNA double-strand break repair. Cancer Res62(10):2766-70 2002

PubMed ID: 12019152

Hu P, Beresten SF, van Brabant AJ, Ye TZ, Pandolfi PP, Johnson FB, Guarente L, Ellis NA, Evidence for BLM and Topoisomerase IIIalpha interaction in genomic stability. Hum Mol Genet10(12):1287-98 2001

PubMed ID: 11406610

Pedrazzi G, Perrera C, Blaser H, Kuster P, Marra G, Davies SL, Ryu GH, Freire R, Hickson ID, Jiricny J, Stagljar I., Direct association of Bloom's syndrome gene product with the human mismatch repair protein MLH1. Nucleic Acids Res29(21):4378-86 2001

PubMed ID: 11691925

Ouellette MM, McDaniel LD, Wright WE, Shay JW, Schultz RA, The establishment of telomerase-immortalized cell lines representing human chromosome instability syndromes. Hum Mol Genet9(3):403-11 2000

PubMed ID: 10655550

Ellis NA, Proytcheva M, Sanz MM, Ye TZ, German J, Transfection of BLM into cultured bloom syndrome cells reduces the sister-chromatid exchange rate toward normal. Am J Hum Genet65(5):1368-74 1999

PubMed ID: 10521302

Neff NF, Ellis NA, Ye TZ, Noonan J, Huang K, Sanz M, Proytcheva M, The DNA helicase activity of BLM is necessary for the correction of the genomic instability of bloom syndrome cells. Mol Biol Cell10:665-76 1999

PubMed ID: 10069810

Prince PR, Ogburn CE, Moser MJ, Emond MJ, Martin GM, Monnat RJ Jr, Cell fusion corrects the 4-nitroquinoline 1-oxide sensitivity of Werner syndrome fibroblast cell lines. Hum Genet105:132-8 1999

PubMed ID: 10480367

Giesler T, Baker K, Zhang B, McDaniel LD, Schultz RA, Correction of the Bloom syndrome cellular phenotypes. Somat Cell Mol Genet23:303-12 1997

PubMed ID: 9546074

Tomkinson AE, Starr R, Schultz RA, DNA ligase III is the major high molecular weight DNA joining activity in SV40-transformed human fibroblasts: normal levels of DNA ligase III activity in Bloom syndrome cells. Nucleic Acids Res21:5425-30 1993

PubMed ID: 8265359

McDaniel LD, Schultz RA, Elevated sister chromatid exchange phenotype of Bloom syndrome cells is complemented by human chromosome 15. Proc Natl Acad Sci U S A89(17):7968-72 1992

PubMed ID: 1518822

Sullivan N, Lyne L, Sensitivity of fibroblasts derived from ataxia-telangiectasia patients to calicheamicin gamma 1I. Mutat Res245:171-5 1990

PubMed ID: 1700294

Mezzina M, Nardelli J, Nocentini S, Remault G, Sarasin A, DNA ligase activity in human cell lines from normal donors and Bloom's syndrome patients. Nucleic Acids Res17:3091-106 1989

PubMed ID: 2726453

Lehmann AR, Willis AE, Broughton BC, James MR, Steingrimsdottir H, Harcourt SA, Arlett CF, Lindahl T, Relation between the human fibroblast strain 46BR and cell lines representative of Bloom's syndrome. Cancer Res48:6343-7 1988

PubMed ID: 3180052

Willis, Structural alterations of DNA ligase I in Bloom syndrome. Proc Natl Acad Sci USA84:8016 (1987):6343-7 1987

PubMed ID: 3180052