ATM, the Mre11/Rad50/Nbs1 Complex, and Topoisomerase I Are Concentrated in the Nucleus of Purkinje Neurons in the Juvenile Human Brain

Overview

Journal DNA Repair (Amst)

Publisher Elsevier

Specialties Biochemistry
Molecular Biology

Date 2007 Aug 21

PMID 17706468

Citations 16

Authors

Elena Gorodetsky

Sarah Calkins

Julia Ahn

P J Brooks

Affiliations

Soon will be listed here.

Abstract

The genetic disease ataxia telangiectasia (AT) results from mutations in the ataxia telangiectasia mutated (ATM) gene. AT patients develop a progressive degeneration of cerebellar Purkinje neurons. Surprisingly, while ATM plays a criticial role in the cellular reponse to DNA damage, previous studies have localized ATM to the cytoplasm of rodent and human Purkinje neurons. Here we show that ATM is primarily localized to the nucleus in cerebellar Purkinje neurons in postmortem human brain tissue samples, although some light cytoplasmic ATM staining was also observed. No ATM staining was observed in brain tissue samples from AT patients, verifying the specificity of the antibody. We also found that antibodies against components of the Mre11/Rad50/Nbs1 (MRN) complex showed strong staining in Purkinje cell nuclei. However, while ATM is present in both the nucleoplasm and nucleolus, MRN proteins are excluded from the nucleolus. We also observed very high levels of topoisomerase 1 (TOP1) in the nucleus, and specifically the nucleolus, of human Purkinje neurons. Our results have direct implications for understanding the mechanisms of neurodegeneration in AT and AT-like disorder.

Citing Articles

In Cerebellar Atrophy of 12-Month-Old ATM-Null Mice, Transcriptome Upregulations Concern Most Neurotransmission and Neuropeptide Pathways, While Downregulations Affect Prominently Itpr1, Usp2 and Non-Coding RNA.

Reichlmeir M, Canet-Pons J, Koepf G, Nurieva W, Duecker R, Doering C Cells. 2023; 12(19).

PMID: 37830614 PMC: 10572167. DOI: 10.3390/cells12192399.

Topoisomerase-Mediated DNA Damage in Neurological Disorders.

Crewe M, Madabhushi R Front Aging Neurosci. 2021; 13:751742.

PMID: 34899270 PMC: 8656403. DOI: 10.3389/fnagi.2021.751742.

Characteristic Eye Movements in Ataxia-Telangiectasia-Like Disorder: An Explanatory Hypothesis.

Federighi P, Ramat S, Rosini F, Pretegiani E, Federico A, Rufa A Front Neurol. 2017; 8:596.

PMID: 29170652 PMC: 5684103. DOI: 10.3389/fneur.2017.00596.

ATM-dependent pathways of chromatin remodelling and oxidative DNA damage responses.

Berger N, Stanley F, Moore S, Goodarzi A Philos Trans R Soc Lond B Biol Sci. 2017; 372(1731).

PMID: 28847820 PMC: 5577461. DOI: 10.1098/rstb.2016.0283.

DNA damage signaling regulates age-dependent proliferative capacity of quiescent inner ear supporting cells.

Laos M, Anttonen T, Kirjavainen A, Af Hallstrom T, Laiho M, Pirvola U Aging (Albany NY). 2014; 6(6):496-510.

PMID: 25063730 PMC: 4100811. DOI: 10.18632/aging.100668.

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