The mitochondrial transcription factor A functions in mitochondrial base excision repair


Autoria(s): CANUGOVI, Chandrika; MAYNARD, Scott; BAYNE, Anne-Cecile V.; SYKORA, Peter; TIAN, Jingyan; SOUZA-PINTO, Nadja C. de; CROTEAU, Deborah L.; BOHR, Vilhelm A.
Contribuinte(s)

UNIVERSIDADE DE SÃO PAULO

Data(s)

20/10/2012

20/10/2012

2010

Resumo

Mitochondrial transcription factor A (TFAM) is an essential component of mitochondrial nucleoids TFAM plays an important role in mitochondrial transcription and replication TFAM has been previously reported to inhibit nucleotide excision repair (NER) in vitro but NER has not yet been detected in mitochondria, whereas base excision repair (BER) has been comprehensively characterized in these organelles The BER proteins are associated with the inner membrane in mitochondria and thus with the mitochondrial nucleoid, where TFAM is also situated However, a function for TFAM in BER has not yet been investigated This study examines the role of TFAM in BER In vitro studies with purified recombinant TFAM indicate that it preferentially binds to DNA containing 8-oxoguanines, but not to abasic sites, uracils, or a gap in the sequence TFAM inhibited the in vitro incision activity of 8-oxoguanine DNA glycosylase (OGG1), uracil-DNA glycosylase (UDG), apurinic endonuclease 1 (APE1), and nucleotide incorporation by DNA polymerase gamma (pol gamma) On the other hand, a DNA binding-defective TFAM mutant, L58A, showed less inhibition of BER in vitro Characterization of TFAM knockdown (KD) cells revealed that these lysates had higher 8oxoG incision activity without changes in alpha OGG1 protein levels TFAM KD cells had mild resistance to menadione and increased damage accumulation in the mtDNA when compared to the control cells In addition, we found that the tumor suppressor p53, which has been shown to interact with and alter the DNA binding activity of TFAM, alleviates TFAM-Induced inhibition of BER proteins Together, the results suggest that TFAM modulates BER in mitochondria by virtue of its DNA binding activity and protein interactions Published by Elsevier B V

National Institute on Aging (NIA/NIH)[Z01-AG000733-14]

National Institute on Aging (NIA/NIH)

Identificador

DNA REPAIR, v.9, n.10, p.1080-1089, 2010

1568-7864

http://producao.usp.br/handle/BDPI/30958

10.1016/j.dnarep.2010.07.009

http://dx.doi.org/10.1016/j.dnarep.2010.07.009

Idioma(s)

eng

Publicador

ELSEVIER SCIENCE BV

Relação

DNA Repair

Direitos

restrictedAccess

Copyright ELSEVIER SCIENCE BV

Palavras-Chave #TFAM #BER #Tumor suppressor #ROS (reactive oxygen species) #8oxoG #OGG1 #FACTOR-A #DNA MUTATIONS #DAMAGED DNA #HUMAN-CELLS #BINDING #TFAM #P53 #DELETIONS #PROTEINS #REPLICATION #Genetics & Heredity #Toxicology
Tipo

article

original article

publishedVersion