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Role of human DNA glycosylase Nei-like 2 (NEIL2) and single strand break repair protein polynucleotide kinase 3'-phosphatase in maintenance of mitochondrial genome.

Journal article
Authors Santi M Mandal
Muralidhar L Hegde
Arpita Chatterjee
Pavana M Hegde
Bartosz Szczesny
Dibyendu Banerjee
Istvan Boldogh
Rui Gao
Maria Falkenberg
Claes M Gustafsson
Partha S Sarkar
Tapas K Hazra
Published in The Journal of biological chemistry
Volume 287
Issue 4
Pages 2819-29
ISSN 1083-351X
Publication year 2012
Published at Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Pages 2819-29
Language en
Links dx.doi.org/10.1074/jbc.M111.272179
Keywords Cytochromes c, genetics, metabolism, DNA Breaks, Single-Stranded, DNA Glycosylases, genetics, metabolism, DNA Repair, physiology, DNA Repair Enzymes, genetics, metabolism, DNA-(Apurinic or Apyrimidinic Site) Lyase, genetics, metabolism, DNA-Directed DNA Polymerase, genetics, metabolism, Genome, Mitochondrial, physiology, HEK293 Cells, Humans, Mitochondria, enzymology, genetics, Mitochondrial Proteins, genetics, metabolism, Phosphotransferases (Alcohol Group Acceptor), genetics, metabolism
Subject categories Basic Medicine

Abstract

The repair of reactive oxygen species-induced base lesions and single strand breaks (SSBs) in the nuclear genome via the base excision (BER) and SSB repair (SSBR) pathways, respectively, is well characterize, and important for maintaining genomic integrity. However, the role of mitochondrial (mt) BER and SSBR proteins in mt genome maintenance is not completely clear. Here we show the presence of the oxidized base-specific DNA glycosylase Nei-like 2 (NEIL2) and the DNA end-processing enzyme polynucleotide kinase 3'-phosphatase (PNKP) in purified human mitochondrial extracts (MEs). Confocal microscopy revealed co-localization of PNKP and NEIL2 with the mitochondrion-specific protein cytochrome c oxidase subunit 2 (MT-CO2). Further, chromatin immunoprecipitation analysis showed association of NEIL2 and PNKP with the mitochondrial genes MT-CO2 and MT-CO3 (cytochrome c oxidase subunit 3); importantly, both enzymes also associated with the mitochondrion-specific DNA polymerase γ. In cell association of NEIL2 and PNKP with polymerase γ was further confirmed by proximity ligation assays. PNKP-depleted ME showed a significant decrease in both BER and SSBR activities, and PNKP was found to be the major 3'-phosphatase in human ME. Furthermore, individual depletion of NEIL2 and PNKP in human HEK293 cells caused increased levels of oxidized bases and SSBs in the mt genome, respectively. Taken together, these studies demonstrate the critical role of NEIL2 and PNKP in maintenance of the mammalian mitochondrial genome.

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