title: ATM, the Mre11/Rad50/Nbs1 complex, and topoisomerase I are concentrated in the nucleus of Purkinje neurons in the juvenile human brain.
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.
authors: Section on Molecular Neurobiology, Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, 5625 Fishers Lane, Room 3S-32, MSC 9412, Bethesda, MD 20952-9412, USA.
authors: Elena
authors: E
authors: Gorodetsky
authors: Sarah
authors: S
authors: Calkins
authors: Julia
authors: J
authors: Ahn
authors: P J
authors: PJ
authors: Brooks
mesh_terms: D017766:Acid Anhydride Hydrolases; D000293:Adolescent; D000328:Adult; D001260:Ataxia Telangiectasia / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins; D001921:Brain / Q000254:growth & development / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000032:analysis* / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000032:analysis / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000032:analysis* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000032:analysis* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D000076228:MRE11 Homologue Protein; D009687:Nuclear Proteins / Q000032:analysis* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000032:analysis* / Q000378:metabolism; D011689:Purkinje Cells / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000032:analysis* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; C112156:NBN protein, human; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D004264:DNA Topoisomerases, Type I; D045643:DNA Repair Enzymes
references: Nat Rev Mol Cell Biol. 2002 Jun;3(6):430-40
references: 12042765
references: J Biol Chem. 2002 May 3;277(18):15661-5
references: 11907023
references: EMBO J. 2003 Oct 15;22(20):5612-21
references: 14532133
references: J Biol Chem. 2004 May 21;279(21):21873-82
references: 15014084
references: DNA Repair (Amst). 2004 Aug-Sep;3(8-9):1141-7
references: 15279803
references: DNA Repair (Amst). 2004 Aug-Sep;3(8-9):1219-25
references: 15279810
references: Brain Res Mol Brain Res. 2004 Sep 10;128(1):1-7
references: 15337312
references: DNA Repair (Amst). 2004 Nov 2;3(11):1515-20
references: 15380107
references: J Comp Neurol. 1976 May 1;167(1):27-47
references: 818132
references: EMBO J. 1985 May;4(5):1237-43
references: 2988941
references: Science. 1995 Jun 23;268(5218):1749-53
references: 7792600
references: Mol Pathol. 1997 Oct;50(5):247-53
references: 9497914
references: Neuroscience. 1998 Oct;86(4):1045-54
references: 9697112
references: Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):10146-51
references: 9707615
references: Neurosci Lett. 1998 Aug 21;252(3):195-8
references: 9739994
references: Semin Pediatr Neurol. 1998 Dec;5(4):287-94
references: 9874856
references: Nat Neurosci. 1999 Feb;2(2):139-43
references: 10195197
references: Science. 1999 Oct 15;286(5439):552-5
references: 10521354
references: Brain Res. 1999 Sep 25;842(2):351-8
references: 10526131
references: J Biol Chem. 2004 Dec 31;279(53):55618-25
references: 15494395
references: Science. 2005 Apr 22;308(5721):551-4
references: 15790808
references: J Comp Neurol. 2005 Dec 19;493(3):357-69
references: 16261531
references: Nat Rev Genet. 2006 May;7(5):373-84
references: 16607398
references: J Biol Chem. 2006 Jun 23;281(25):17482-91
references: 16627474
references: J Neurosci. 2006 Jul 19;26(29):7767-74
references: 16855104
references: Cold Spring Harb Symp Quant Biol. 2005;70:99-109
references: 16869743
references: Neuroscience. 2006 Sep 15;141(4):1951-9
references: 16784818
references: Nature. 2006 Sep 14;443(7108):222-5
references: 16906133
references: Nat Rev Cancer. 2006 Oct;6(10):789-802
references: 16990856
references: J Comp Neurol. 2007 Jan 1;500(1):71-83
references: 17099896
references: DNA Repair (Amst). 2007 Jan 4;6(1):128-34
references: 17178256
references: Trends Biochem Sci. 2006 Jul;31(7):402-10
references: 16774833
references: J Biol Chem. 1999 Nov 26;274(48):34277-82
references: 10567403
references: Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):871-6
references: 10639172
references: Adv Cancer Res. 2001;80:189-216
references: 11034544
references: J Comp Neurol. 2001 Mar 5;431(2):228-39
references: 11170002
references: J Neurosci. 2001 Sep 1;21(17):6687-93
references: 11517258
references: Nat Genet. 2002 Oct;32(2):267-72
references: 12244316