Increased SOD1 association with chromatin, DNA damage, p53 activation, and apoptosis in a cellular model of SOD1-linked ALS

Livea F. Barbosa, Fernanda M. Cerqueira, Antero F A Macedo, Camila C M Garcia, José Pedro F Angeli, Robert I. Schumacher, Mari Cleide Sogayar, Ohara Augusto, Maria Teresa Carrí, Paolo Di Mascio, Marisa H G Medeiros

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Mutations in the gene encoding cytosolic Cu,Zn-superoxide dismutase (SOD1) have been linked to familial amyotrophic lateral sclerosis (FALS). However the molecular mechanisms of motor neuron death are multi-factorial and remain unclear. Here we examined DNA damage, p53 activity and apoptosis in SH-SY5Y human neuroblastoma cells transfected to achieve low-level expression of either wild-type or mutant Gly93→Ala (G93A) SOD1, typical of FALS. DNA damage was investigated by evaluating the levels of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodGuo) and DNA strand breaks. Significantly higher levels of DNA damage, increased p53 activity, and a greater percentage of apoptotic cells were observed in SH-SY5Y cells transfected with G93A SOD1 when compared to cells overexpressing wild-type SOD1 and untransfected cells. Western blot, FACS, and confocal microscopy analysis demonstrated that G93A SOD1 is present in the nucleus in association with DNA. Nuclear G93A SOD1 has identical superoxide dismutase activity but displays increased peroxidase activity when compared to wild-type SOD1. These results indicate that the G93A mutant SOD1 association with DNA might induce DNA damage and trigger the apoptotic response by activating p53. This toxic activity of mutant SOD1 in the nucleus may play an important role in the complex mechanisms associated with motor neuron death observed in ALS pathogenesis.

Original languageEnglish
Pages (from-to)462-471
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1802
Issue number5
DOIs
Publication statusPublished - May 2010

Fingerprint

DNA Damage
Chromatin
Apoptosis
Motor Neurons
DNA Breaks
Poisons
DNA
Neuroblastoma
Confocal Microscopy
Peroxidase
Superoxide Dismutase
Western Blotting
Mutation
Genes
Amyotrophic lateral sclerosis 1

Keywords

  • ALS
  • DNA damage
  • Nucleus
  • P53
  • SOD1

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine

Cite this

Barbosa, L. F., Cerqueira, F. M., Macedo, A. F. A., Garcia, C. C. M., Angeli, J. P. F., Schumacher, R. I., ... Medeiros, M. H. G. (2010). Increased SOD1 association with chromatin, DNA damage, p53 activation, and apoptosis in a cellular model of SOD1-linked ALS. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1802(5), 462-471. https://doi.org/10.1016/j.bbadis.2010.01.011

Increased SOD1 association with chromatin, DNA damage, p53 activation, and apoptosis in a cellular model of SOD1-linked ALS. / Barbosa, Livea F.; Cerqueira, Fernanda M.; Macedo, Antero F A; Garcia, Camila C M; Angeli, José Pedro F; Schumacher, Robert I.; Sogayar, Mari Cleide; Augusto, Ohara; Carrí, Maria Teresa; Di Mascio, Paolo; Medeiros, Marisa H G.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1802, No. 5, 05.2010, p. 462-471.

Research output: Contribution to journalArticle

Barbosa, LF, Cerqueira, FM, Macedo, AFA, Garcia, CCM, Angeli, JPF, Schumacher, RI, Sogayar, MC, Augusto, O, Carrí, MT, Di Mascio, P & Medeiros, MHG 2010, 'Increased SOD1 association with chromatin, DNA damage, p53 activation, and apoptosis in a cellular model of SOD1-linked ALS', Biochimica et Biophysica Acta - Molecular Basis of Disease, vol. 1802, no. 5, pp. 462-471. https://doi.org/10.1016/j.bbadis.2010.01.011
Barbosa, Livea F. ; Cerqueira, Fernanda M. ; Macedo, Antero F A ; Garcia, Camila C M ; Angeli, José Pedro F ; Schumacher, Robert I. ; Sogayar, Mari Cleide ; Augusto, Ohara ; Carrí, Maria Teresa ; Di Mascio, Paolo ; Medeiros, Marisa H G. / Increased SOD1 association with chromatin, DNA damage, p53 activation, and apoptosis in a cellular model of SOD1-linked ALS. In: Biochimica et Biophysica Acta - Molecular Basis of Disease. 2010 ; Vol. 1802, No. 5. pp. 462-471.
@article{cdfe9bcd934a4231b7b1acacbcc70a8c,
title = "Increased SOD1 association with chromatin, DNA damage, p53 activation, and apoptosis in a cellular model of SOD1-linked ALS",
abstract = "Mutations in the gene encoding cytosolic Cu,Zn-superoxide dismutase (SOD1) have been linked to familial amyotrophic lateral sclerosis (FALS). However the molecular mechanisms of motor neuron death are multi-factorial and remain unclear. Here we examined DNA damage, p53 activity and apoptosis in SH-SY5Y human neuroblastoma cells transfected to achieve low-level expression of either wild-type or mutant Gly93→Ala (G93A) SOD1, typical of FALS. DNA damage was investigated by evaluating the levels of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodGuo) and DNA strand breaks. Significantly higher levels of DNA damage, increased p53 activity, and a greater percentage of apoptotic cells were observed in SH-SY5Y cells transfected with G93A SOD1 when compared to cells overexpressing wild-type SOD1 and untransfected cells. Western blot, FACS, and confocal microscopy analysis demonstrated that G93A SOD1 is present in the nucleus in association with DNA. Nuclear G93A SOD1 has identical superoxide dismutase activity but displays increased peroxidase activity when compared to wild-type SOD1. These results indicate that the G93A mutant SOD1 association with DNA might induce DNA damage and trigger the apoptotic response by activating p53. This toxic activity of mutant SOD1 in the nucleus may play an important role in the complex mechanisms associated with motor neuron death observed in ALS pathogenesis.",
keywords = "ALS, DNA damage, Nucleus, P53, SOD1",
author = "Barbosa, {Livea F.} and Cerqueira, {Fernanda M.} and Macedo, {Antero F A} and Garcia, {Camila C M} and Angeli, {Jos{\'e} Pedro F} and Schumacher, {Robert I.} and Sogayar, {Mari Cleide} and Ohara Augusto and Carr{\'i}, {Maria Teresa} and {Di Mascio}, Paolo and Medeiros, {Marisa H G}",
year = "2010",
month = "5",
doi = "10.1016/j.bbadis.2010.01.011",
language = "English",
volume = "1802",
pages = "462--471",
journal = "Biochimica et Biophysica Acta - Molecular Basis of Disease",
issn = "0925-4439",
publisher = "Elsevier",
number = "5",

}

TY - JOUR

T1 - Increased SOD1 association with chromatin, DNA damage, p53 activation, and apoptosis in a cellular model of SOD1-linked ALS

AU - Barbosa, Livea F.

AU - Cerqueira, Fernanda M.

AU - Macedo, Antero F A

AU - Garcia, Camila C M

AU - Angeli, José Pedro F

AU - Schumacher, Robert I.

AU - Sogayar, Mari Cleide

AU - Augusto, Ohara

AU - Carrí, Maria Teresa

AU - Di Mascio, Paolo

AU - Medeiros, Marisa H G

PY - 2010/5

Y1 - 2010/5

N2 - Mutations in the gene encoding cytosolic Cu,Zn-superoxide dismutase (SOD1) have been linked to familial amyotrophic lateral sclerosis (FALS). However the molecular mechanisms of motor neuron death are multi-factorial and remain unclear. Here we examined DNA damage, p53 activity and apoptosis in SH-SY5Y human neuroblastoma cells transfected to achieve low-level expression of either wild-type or mutant Gly93→Ala (G93A) SOD1, typical of FALS. DNA damage was investigated by evaluating the levels of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodGuo) and DNA strand breaks. Significantly higher levels of DNA damage, increased p53 activity, and a greater percentage of apoptotic cells were observed in SH-SY5Y cells transfected with G93A SOD1 when compared to cells overexpressing wild-type SOD1 and untransfected cells. Western blot, FACS, and confocal microscopy analysis demonstrated that G93A SOD1 is present in the nucleus in association with DNA. Nuclear G93A SOD1 has identical superoxide dismutase activity but displays increased peroxidase activity when compared to wild-type SOD1. These results indicate that the G93A mutant SOD1 association with DNA might induce DNA damage and trigger the apoptotic response by activating p53. This toxic activity of mutant SOD1 in the nucleus may play an important role in the complex mechanisms associated with motor neuron death observed in ALS pathogenesis.

AB - Mutations in the gene encoding cytosolic Cu,Zn-superoxide dismutase (SOD1) have been linked to familial amyotrophic lateral sclerosis (FALS). However the molecular mechanisms of motor neuron death are multi-factorial and remain unclear. Here we examined DNA damage, p53 activity and apoptosis in SH-SY5Y human neuroblastoma cells transfected to achieve low-level expression of either wild-type or mutant Gly93→Ala (G93A) SOD1, typical of FALS. DNA damage was investigated by evaluating the levels of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodGuo) and DNA strand breaks. Significantly higher levels of DNA damage, increased p53 activity, and a greater percentage of apoptotic cells were observed in SH-SY5Y cells transfected with G93A SOD1 when compared to cells overexpressing wild-type SOD1 and untransfected cells. Western blot, FACS, and confocal microscopy analysis demonstrated that G93A SOD1 is present in the nucleus in association with DNA. Nuclear G93A SOD1 has identical superoxide dismutase activity but displays increased peroxidase activity when compared to wild-type SOD1. These results indicate that the G93A mutant SOD1 association with DNA might induce DNA damage and trigger the apoptotic response by activating p53. This toxic activity of mutant SOD1 in the nucleus may play an important role in the complex mechanisms associated with motor neuron death observed in ALS pathogenesis.

KW - ALS

KW - DNA damage

KW - Nucleus

KW - P53

KW - SOD1

UR - http://www.scopus.com/inward/record.url?scp=77950369529&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77950369529&partnerID=8YFLogxK

U2 - 10.1016/j.bbadis.2010.01.011

DO - 10.1016/j.bbadis.2010.01.011

M3 - Article

C2 - 20097285

AN - SCOPUS:77950369529

VL - 1802

SP - 462

EP - 471

JO - Biochimica et Biophysica Acta - Molecular Basis of Disease

JF - Biochimica et Biophysica Acta - Molecular Basis of Disease

SN - 0925-4439

IS - 5

ER -