GM03395

GM03395 Fibroblast

Description:

ATAXIA-TELANGIECTASIA; AT
ATAXIA-TELANGIECTASIA MUTATED GENE; ATM

Affected:

Yes

Sex:

Male

Age:

13 YR (At Sampling)

Overview

Repository

NIGMS Human Genetic Cell Repository

Subcollection

Heritable Diseases
Hereditary Cancers
Chromosome Abnormalities

Class

Repair Defective and Chromosomal Instability Syndromes

Class

Syndromes with Increased Chromosome Breakage

Cell Type

Fibroblast

Transformant

Untransformed

Race

Black/African American

Family Member

Relation to Proband

proband

Confirmation

Clinical summary/Case history

Species

Homo sapiens

Common Name

Human

Remarks

Clinically affected; increased sensitivity to cell killing by X-irradiation; lymphoid culture shows hypersensitivity to X-irradiation; donor subject is homozygous for a G>A transition at nucleotide 7913 in exon 55 of the ATM gene (7913G>A) resulting in a substitution of a termination codon for tryptophan at codon 2638 [Trp2638Ter (W2638X)]; a deceased sister also had AT; parents are GM03396 and GM03397; same donor as GM03332 Lymphoblast.

Characterizations

PDL at Freeze

4.7

Passage Frozen

IDENTIFICATION OF SPECIES OF ORIGIN

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

REPAIR OF UV- OR X RAY-IRRADIATED DNA OR ALKYLATED DNA

Nagasawa et al (Cancer Res 47:398-402,1987) observed that this cell culture derived from an Ataxia telangiectasia homozygote showed a hypersensitive response to the cytotoxic effects of X-irradiation. Bennett & Rainbow (Mutagenesis 3:389-395,1988) examined the UV-enhanced reactivation (UVER) and UV-enhanced mutagenesis (UVEM) of UVirradiated adenovirus in AT fibroblasts. UVER was examined using both V antigen expression as well as progeny production from infected cultures. Viral mutagenesis was studied by examining the induction of phenotypically wild-type revertants among the progeny obtained from fibroblasts infected with a temperature-sensitive early mutant of adenovirus (Ad5ts36). UVER factors for Ad V antigen expression were significantly less than normal in the AT strains tested when infection occurred immediately after UV-irradiation of cells. However, UVER factors were >1 and similar to those found for normal strains when cells were infected 24 h after UV-irradiation, indicating a delay in the expression of UVER for Ad V antigen in AT cells. UV-irradiation of both normal and AT cells 24 h prior to infection also resulted in a significant increase in progeny survival for UV-irradiated Ad. In normal cells, this progeny UVER was concomitant with a significant increase in the mutation frequency for UV-irradiated virus (increase in targeted mutagenesis) suggesting the existence of an inducible errorprone DNA repair mode in normal human cells. In contrast, pre-UV-irradiation of AT cells resulted in a significant decrease in the mutation frequency for UV-irradiated virus. These results suggest that AT cells lack an inducible error-prone DNA mode and that the delayed expression of UVER in AT cells results from a relatively error-free mechanism.

Gene

ATM

Chromosomal Location

11q22.3

Allelic Variant 1

W2638X; ATAXIA-TELANGIECTASIA

Identified Mutation

TRP2638TER

Gene

ATM

Chromosomal Location

11q22.3

Allelic Variant 2

W2638X; ATAXIA-TELANGIECTASIA

Identified Mutation

TRP2638TER

Phenotypic Data

Remarks

Publications

Liu X, Hu M, Liu P, Jiao M, Zhou M, Lee AK, Li F, Li CY, ATM Paradoxically Promotes Oncogenic Transformation via Transcriptional Reprogramming Cancer research: 2020

PubMed ID: 32060145

Innes CL, Heinloth AN, Flores KG, Sieber SO, Deming PB, Bushel PR, Kaufmann WK, Paules RS, ATM requirement in gene expression responses to ionizing radiation in human lymphoblasts and fibroblasts. Mol Cancer Res4(3):197-207 2006

PubMed ID: 16547157

Castillo JP, Frame FM, Rogoff HA, Pickering MT, Yurochko AD, Kowalik TF, Human cytomegalovirus IE1-72 activates ataxia telangiectasia mutated kinase and a p53/p21-mediated growth arrest response Journal of virology79:11467-75 2005

PubMed ID: 16103197

Ha L, Ceryak S, Patierno SR, Generation of S phase-dependent DNA double strand breaks by Cr(VI) exposure: involvement of ATM in Cr(VI) induction of {gamma}-H2AX. CarcinogenesisEpub ahead of print:11467-75 2004

PubMed ID: 15284180

Ismail SM, Buchholz TA, Story M, Brock WA, Stevens CW, Radiosensitivity is predicted by DNA end-binding complex density, but not by nuclear levels of band components. Radiother Oncol72(3):325-32 2004

PubMed ID: 15450732

Rogoff HA, Pickering MT, Frame FM, Debatis ME, Sanchez Y, Jones S, Kowalik TF, Apoptosis associated with deregulated E2F activity is dependent on E2F1 and Atm/Nbs1/Chk2. Mol Cell Biol24(7):2968-77 2004

PubMed ID: 15024084

Ha L, Ceryak S, Patierno SR, Chromium (VI) activates ataxia telangiectasia mutated (ATM) protein. Requirement of ATM for both apoptosis and recovery from terminal growth arrest. J Biol Chem278(20):17885-94 2003

PubMed ID: 12637545

Deming PB, Flores KG, Downes CS, Paules RS, Kaufmann WK, ATR enforces the topoisomerase II-dependent G2 checkpoint through inhibition of Plk1 kinase. J Biol Chem277(39):36832-8 2002

PubMed ID: 12147700

Gueven N, Keating KE, Chen P, Fukao T, Khanna KK, Watters D, Rodemann PH, Lavin MF, Epidermal growth factor sensitizes cells to ionizing radiation by down-regulating protein mutated in ataxia-telangiectasia. J Biol Chem276(12):8884-91 2001

PubMed ID: 11080496

Keating KE, Gueven N, Watters D, Rodemann HP, Lavin MF, Transcriptional downregulation of ATM by EGF is defective in ataxia-telangiectasia cells expressing mutant protein. Oncogene20(32):4281-90 2001

PubMed ID: 11466608

Shackelford RE, Innes CL, Sieber SO, Heinloth AN, Leadon SA, Paules RS, The Ataxia telangiectasia gene product is required for oxidative stress-induced G1 and G2 checkpoint function in human fibroblasts. J Biol Chem276(24):21951-9 2001

PubMed ID: 11290740

Yih LH, Lee TC, Arsenite induces p53 accumulation through an ATM-dependent pathway in human fibroblasts. Cancer Res60(22):6346-52 2000

PubMed ID: 11103796

Ashburner BP, Shackelford RE, Baldwin AS Jr, Paules RS, Lack of involvement of ataxia telangiectasia mutated (ATM) in regulation of nuclear factor-kappaB (NF-kappaB) in human diploid fibroblasts. Cancer Res59(21):5456-60 1999

PubMed ID: 10554017

Wang XW, Zhan Q, Coursen JD, Khan MA, Kontny HU, Yu L, Hollander MC, O'Connor PM, Fornace AJ Jr, Harris CC, GADD45 induction of a G2/M cell cycle checkpoint. Proc Natl Acad Sci U S A96:3706-11 1999

PubMed ID: 10097101

Rhodes N, D'Souza T, Foster CD, Ziv Y, Kirsch DG, Shiloh Y, Kastan MB, Reinhart PH, Gilmer TM, Defective potassium currents in ataxia telangiectasia fibroblasts. Genes Dev12:3686-92 1998

PubMed ID: 9851975

Vaziri H, West MD, Allsopp RC, Davison TS, Wu YS, Arrowsmith CH, Poirier GG, Benchimol S, ATM-dependent telomere loss in aging human diploid fibroblasts and DNA damage lead to the post-translational activation of p53 protein involving poly(ADP-ribose) polymerase. EMBO J16:6018-33 1997

PubMed ID: 9312059

Chen G, Lee EYHP, The product of the ATM gene is a 370-kDa nuclear phosphoprotein. J Biol Chem271:33693-7 1996

PubMed ID: 8969240

Lu X, Lane DP, Differential induction of transcriptionally active p53 following UV or ionizing radiation: defects in chromosome instability syndromes? Cell75:765-78 1993

PubMed ID: 8242748

Kastan MB, Zhan Q, el-Deiry WS, Carrier F, Jacks T, Walsh WV, Plunkett BS, Vogelstein B, Fornace AJ Jr, A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell71:587-97 1992

PubMed ID: 1423616

Taylor YC, Duncan PG, Zhang X, Wright WD, Differences in the DNA supercoiling response of irradiated cell lines from ataxia-telangiectasia versus unaffected individuals. Int J Radiat Biol59:359-71 1991

PubMed ID: 1671687

Taylor YC, Zhang XF, Parsian AJ, Duncan PG, Image analysis-based measurement of DNA supercoiling changes in transformed and nontransformed human cell lines. Exp Cell Res197:222-8 1991

PubMed ID: 1659987

Bender MA, Viola MV, Fiore J, Thompson MH, Leonard RC, Normal G2 chromosomal radiosensitivity and cell survival in the cancer family syndrome [see comments] Cancer Res48:2579-84 1988

PubMed ID: 3356018

Bennett CB, Rainbow AJ, Delayed expression of enhanced reactivation and decreased mutagenesis of UV-irradiated adenovirus in UV-irradiated ataxia telangiectasia fibroblasts. Mutagenesis3:389-95 1988

PubMed ID: 3070272

Nagasawa H, Kraemer KH, Shiloh Y, Little JB, Detection of ataxia telangiectasia heterozygous cell lines by postirradiation cumulative labeling index: measurements with coded samples. Cancer Res47:398-402 1987

PubMed ID: 3791230

Jeeves WP, Rainbow AJ, An aberration in gamma-ray-enhanced reactivation of irradiated adenovirus in ataxia telangiectasia fibroblasts. Carcinogenesis7:381-7 1986

PubMed ID: 3948323

Berliner N, Duby AD, Morton CC, Leder P, Seidman JG, Detection of a frequent restriction fragment length polymorphism in the human T cell antigen receptor beta chain locus. A potential diagnostic tool. J Clin Invest76:1283-5 1985

PubMed ID: 2995449

Nagasawa H, Latt SA, Lalande ME, Little JB, Effects of X-irradiation on cell-cycle progression, induction of chromosomal aberrations and cell killing in ataxia telangiectasia (AT) fibroblasts. Mutat Res148:71-82 1985

PubMed ID: 3969079

Boorstein RJ, Pardee AB, Factors modifying 3-aminobenzamide cytotoxicity in normal and repair- deficient human fibroblasts. J Cell Physiol120:335-44 1984

PubMed ID: 6746752

Kinsella TJ, Mitchell JB, McPherson S, Russo A, Tietze F, In vitro X-ray sensitivity in ataxia telangiectasis homozygote and heterozygote skin fibroblasts under oxic and hypoxic conditions. Cancer Res42:3950-6 1982

PubMed ID: 7104995