The polymorphic AluYb8 insertion in the MUTYH gene is associated with reduced type 1 protein expression and reduced mitochondrial DNA content

The human mutY homolog (MUTYH) participates in base excision repair (BER), which is critical for repairing oxidized DNA bases and maintaining DNA replication fidelity. The polymorphic AluYb8 insertion in the 15(th) intron of the MUTYH gene (AluYb8MUTYH) has been shown to associate with an aggregated...

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Bibliographic Details
Published in:PloS one 2013-08, Vol.8 (8), p.e70718
Main Authors: Guo, Wenwen, Zheng, Bixia, Cai, Zhenming, Xu, Lizhi, Guo, Dong, Cao, Lili, Wang, Yaping
Format: Article
Language:English
Subjects:
Adult
Age
Amino acids
Base excision repair
Base Sequence
Biology
Cell cycle
Cell Respiration - genetics
Deoxyguanosine
Deoxyribonucleic acid
DNA
DNA biosynthesis
DNA Glycosylases - genetics
DNA repair
DNA Repair - genetics
DNA replication
DNA, Mitochondrial - metabolism
E coli
Enzymes
Escherichia coli
Female
Fibroblasts - cytology
Fibroblasts - metabolism
Gene expression
Gene Expression Regulation, Enzymologic - genetics
Genes
Genetic aspects
Health risks
Heterozygote
Homeostasis
Homology
Homozygote
Humans
Insertion
Introns - genetics
Laboratories
Leukocytes, Mononuclear - metabolism
Localization
Maintenance
Male
Medicine
Mitochondria
Mitochondrial DNA
Molecular Sequence Data
Mutagenesis, Insertional
Mutation
Oxygen - metabolism
Polymorphism, Genetic - genetics
Protein Isoforms - genetics
Proteins
Repair
Risk factors
RNA, Messenger - genetics
RNA, Messenger - metabolism
Transcription, Genetic - genetics
Young Adult
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Summary:The human mutY homolog (MUTYH) participates in base excision repair (BER), which is critical for repairing oxidized DNA bases and maintaining DNA replication fidelity. The polymorphic AluYb8 insertion in the 15(th) intron of the MUTYH gene (AluYb8MUTYH) has been shown to associate with an aggregated 8-hydroxy-2'-deoxyguanosine (8-OH-dG) lesion in genomic DNA and to serve as a risk factor for age-related diseases. In this work, we demonstrate that this variant is associated with a significant reduction of the type 1 MUTYH protein that localizes to mitochondria. Notably, this variant affects mitochondrial DNA (mtDNA) maintenance and functional mitochondrial mass in individuals homozygous for the AluYb8MUTYH variant. These findings provide evidence for an association between the AluYb8MUTYH variant and decreased mitochondrial homeostasis and, consequently, contribute to elucidating the roles of the AluYb8MUTYH variant in impairing the mitochondrial base excision repair (mtBER) system and increasing the risk of acquiring an age-related disease.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0070718