Base excision repair in nuclear and mitochondrial DNA.
Base excision repair mechanisms have been analyzed in nuclear and mitochondrial DNA. We measured the size and position of the newly incorporated DNA repair patch in various DNA substrates containing single oxidative lesions. Repair of 8-oxoguanine and of thymine glycol is almost exclusively via the base excision repair (BER) pathway with little or no involvement of nucleotide excision repair (NER). The repair mode is generally via the single-nucleotide replacement pathway with little incorporation into longer patches. Extension of these studies suggests that DNA polymerase beta plays a critical role not only in the short-patch repair process but also in the long-patch, PCNA-dependent pathway. Mitochondria are targets for a heavy load of oxidative DNA damage. They have efficient BER repair capacity, but cannot repair most bulky lesions normally repaired by NER. In vitro experiments performed using rat and human mitochondrial extracts suggest that the repair incorporation during the removal of uracil in DNA occurs via the short-patch repair BER pathway. Oxidative DNA damage accumulates with age in mitochondrial DNA, but this cannot be explained by an attenuation of DNA repair. In contrast, we observe that mitochondrial incision of 8-oxoG increases with age in rodents.
Dianov
G L
GL
Laboratory of Molecular Genetics, National Institute on Aging, NIH Baltimore, Maryland 21224, USA.
Souza-Pinto
N
N
Nyaga
S G
SG
Thybo
T
T
Stevnsner
T
T
Bohr
V A
VA
D000225:Adenine / Q000031:analogs & derivatives* / Q000378:metabolism; D000375:Aging / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D002474:Cell-Free System; D004247:DNA / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D045647:DNA Glycosylases; D019951:DNA Polymerase beta / Q000502:physiology; D004260:DNA Repair; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D043382:DNA-Formamidopyrimidine Glycosylase; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D019271:Hypoxanthine / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism / Q000648:ultrastructure; D008322:Mammals / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000201:enzymology; D008969:Molecular Sequence Data; D009699:N-Glycosyl Hydrolases / Q000502:physiology; D016877:Oxidants / Q000633:toxicity; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017354:Point Mutation; D018809:Proliferating Cell Nuclear Antigen / Q000502:physiology; D051381:Rats; D013941:Thymine / Q000031:analogs & derivatives* / Q000378:metabolism
D004272:DNA, Mitochondrial; D016877:Oxidants; D018809:Proliferating Cell Nuclear Antigen; C004981:1,N(6)-ethenoadenine; C029389:thymine glycol; D019271:Hypoxanthine; C025946:3-methyladenine; C024829:8-hydroxyguanine; D006147:Guanine; D004247:DNA; D019951:DNA Polymerase beta; C021565:3-methyladenine-DNA glycosylase; D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; D043382:DNA-Formamidopyrimidine Glycosylase; D000225:Adenine; D013941:Thymine