Analysis of chromosomal aberrations and γH2A.X foci to identify radiation-sensitive ataxia-telangiectasia patients

被引：13

作者：

Bucher, Martin ^{[1
]}

Endesfelder, David ^{[1
]}

Roessler, Ute ^{[1
]}

Borkhardt, Arndt ^{[2
]}

Dueckers, Gregor ^{[3
]}

Kirlum, Hans-Joachim ^{[4
]}

Lankisch, Petra ^{[2
]}

Oommen, Prasad T. ^{[2
]}

Niehues, Tim ^{[3
]}

Ruebe, Claudia E. ^{[5
,6
]}

Baumgartner, Ingrid ^{[1
]}

Bunk, Frank ^{[1
]}

Moertl, Simone ^{[1
]}

Hornhardt, Sabine ^{[1
]}

Gomolka, Maria ^{[1
]}

机构：

[1] Fed Off Radiat Protect, Dept Effects & Risks Ionising & Nonionising Radia, Ingolstadter Landstr 1, D-85764 Oberschleissheim, Germany

[2] Heinrich Heine Univ Dusseldorf, Dept Pediat Oncol Hematol & Clin Immunol, Med Fac, Ctr Child & Adolescent Hlth, Moorenstr 5, D-40225 Dusseldorf, Germany

[3] HELIOS Hosp Krefeld, Ctr Child & Adolescent Hlth, Lutherpl 40, D-47805 Krefeld, Germany

[4] Pediat Surg & Pediat Orthoped Au, Kuhbachstr 1, D-81543 Munich, Germany

[5] Saarland Univ Hosp, Dept Radiotherapy & Radiat Oncol, Kirrberger Str,Bldg 6-5, D-66421 Homburg, Germany

[6] Saarland Univ, Fac Med, Kirrberger Str,Bldg 6-5, D-66421 Homburg, Germany

来源：

MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS | 2021年 / 861卷

关键词：

Ataxia-telangiectasia; Radiation sensitivity; H2A.X; mFISH; Chromosomal aberrations; Biomarker; ATM PROTEIN; DNA-DAMAGE; HIGH-FREQUENCY; CELLS; GENE; MUTATIONS; CANCER; REPAIR; RADIOSENSITIVITY; LYMPHOCYTES;

D O I：

10.1016/j.mrgentox.2020.503301

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

Ataxia-telangiectasia (AT) is a rare inherited recessive disorder which is caused by a mutated Ataxia-telangiectasia mutated (ATM) gene. Hallmarks include chromosomal instability, cancer predisposition and increased sensitivity to ionizing radiation. The ATM protein plays an important role in signaling of DNA double-strand breaks (DSB), thereby phosphorylating the histone H2A.X. Non-functional ATM protein leads to defects in DNA damage response, unresolved DSBs and genomic instability. The aim of this study was to evaluate chromosomal aberrations and gamma H2A.X foci as potential radiation sensitivity biomarkers in AT patients. For this purpose, lymphocytes of 8 AT patients and 10 healthy controls were irradiated and induced DNA damage and DNA repair capacity were detected by the accumulation of gamma H2A.X foci. The results were heterogeneous among AT patients. Evaluation revealed 2 AT patients with similar gamma H2A.X foci numbers as controls after 1 h while 3 patients showed a lower induction. In regard to DNA repair, 3 of 5 AT patients showed poor damage repair. Therefore, DNA damage induction and DNA repair as detected by H2A.X phosphorylation revealed individual differences, seems to depend on the underlying individual mutation and thus appears not well suited as a biomarker for radiation sensitivity. In addition, chromosomal aberrations were analyzed by mFISH. An increased frequency of spontaneous chromosomal breakage was characteristic for AT cells. After irradiation, significantly increased rates for non-exchange aberrations, translocations, complex aberrations and dicentric chromosomes were observed in AT patients compared to controls. The results of this study suggested, that complex aberrations and dicentric chromosomes might be a reliable biomarker for radiation sensitivity in AT patients, while non-exchange aberrations and translocations identified both, spontaneous and radiation-induced chromosomal instability.

引用

页数：13

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