TY - JOUR
T1 - Oxidative genome damage and its repair
T2 - Implications in aging and neurodegenerative diseases
AU - Hegde, Muralidhar L.
AU - Mantha, Anil K.
AU - Hazra, Tapas K.
AU - Bhakat, Kishor K.
AU - Mitra, Sankar
AU - Szczesny, Bartosz
N1 - Funding Information:
The research in the authors’ laboratory is supported by USPHS grants R01 CA81063 , R01 CA53791 , P01 CA92586 , P01 AG10514 , P30 ES06676 (SM) , R01 CA102271 (TKH) and American Parkinson's Disease Association's postdoctoral fellowship (MLH). Because of the limited focus of the article, many appropriate references could not be included, for which the authors apologize. We thank Drs. KSJ Rao (INDICASAT-AIP, Panama) and Istvan Boldogh (Department of Microbiology and Immunology, UTMB) for helpful discussions.
PY - 2012/4
Y1 - 2012/4
N2 - Reactive oxygen species (ROS), generated endogenously during respiration or exogenously by genotoxic agents, induce oxidized bases and single-strand breaks (SSBs) in DNA that are repaired . via the base excision/SSB repair (BER/SSBR) pathway in both the nucleus and mitochondria. Tightly regulated BER/SSBR with multiple sub-pathways is highly complex, and is linked to the replication and transcription. The repair-initiating DNA glycosylases (DGs) or AP-endonuclease (APE1) control the sub-pathway by stably interacting with downstream proteins usually . via their common interacting domain (CID). A nonconserved CID with disordered structure usually located at one of the termini includes the sequences for covalent modifications and/or organelle targeting. While the DGs are individually dispensable, the SSBR-initiating APE1 and polynucleotide kinase 3' phosphatase (PNKP) are essential. BER/SSBR of mammalian nuclear and mitochondrial genomes share the same early enzymes. Accumulation of oxidative damage in nuclear and mitochondrial genomes has been implicated in aging and various neurological disorders. While defects in BER/SSBR proteins have been linked to hereditary neurodegenerative diseases, our recent studies implicated transition metal-induced inhibition of NEIL family DGs in sporadic diseases. This review focuses on the recent advances in repair of oxidatively damages in mammalian genomes and their linkage to aging and neurological disorders.
AB - Reactive oxygen species (ROS), generated endogenously during respiration or exogenously by genotoxic agents, induce oxidized bases and single-strand breaks (SSBs) in DNA that are repaired . via the base excision/SSB repair (BER/SSBR) pathway in both the nucleus and mitochondria. Tightly regulated BER/SSBR with multiple sub-pathways is highly complex, and is linked to the replication and transcription. The repair-initiating DNA glycosylases (DGs) or AP-endonuclease (APE1) control the sub-pathway by stably interacting with downstream proteins usually . via their common interacting domain (CID). A nonconserved CID with disordered structure usually located at one of the termini includes the sequences for covalent modifications and/or organelle targeting. While the DGs are individually dispensable, the SSBR-initiating APE1 and polynucleotide kinase 3' phosphatase (PNKP) are essential. BER/SSBR of mammalian nuclear and mitochondrial genomes share the same early enzymes. Accumulation of oxidative damage in nuclear and mitochondrial genomes has been implicated in aging and various neurological disorders. While defects in BER/SSBR proteins have been linked to hereditary neurodegenerative diseases, our recent studies implicated transition metal-induced inhibition of NEIL family DGs in sporadic diseases. This review focuses on the recent advances in repair of oxidatively damages in mammalian genomes and their linkage to aging and neurological disorders.
KW - Aging
KW - DNA base excision repair
KW - DNA glycosylases
KW - Neurodegenerative disorders
KW - Protein-protein and protein-DNA interactions
KW - Reactive oxygen species
KW - Single-strand break repair
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U2 - 10.1016/j.mad.2012.01.005
DO - 10.1016/j.mad.2012.01.005
M3 - Article
C2 - 22313689
AN - SCOPUS:84860704002
SN - 0047-6374
VL - 133
SP - 157
EP - 168
JO - Mechanisms of Ageing and Development
JF - Mechanisms of Ageing and Development
IS - 4
ER -