PMID- 29879444
OWN - NLM
STAT- MEDLINE
DCOM- 20191001
LR  - 20230928
IS  - 1873-4596 (Electronic)
IS  - 0891-5849 (Print)
IS  - 0891-5849 (Linking)
VI  - 124
DP  - 2018 Aug 20
TI  - Enhanced mitochondrial DNA repair of the common disease-associated variant, 
      Ser326Cys, of hOGG1 through small molecule intervention.
PG  - 149-162
LID - S0891-5849(18)30975-4 [pii]
LID - 10.1016/j.freeradbiomed.2018.05.094 [doi]
AB  - The common oxidatively generated lesion, 8-oxo-7,8-dihydroguanine (8-oxoGua), is 
      removed from DNA by base excision repair. The glycosylase primarily charged with 
      recognition and removal of this lesion is 8-oxoGuaDNA glycosylase 1 (OGG1). When 
      left unrepaired, 8-oxodG alters transcription and is mutagenic. Individuals 
      homozygous for the less active OGG1 allele, Ser326Cys, have increased risk of 
      several cancers. Here, small molecule enhancers of OGG1 were identified and 
      tested for their ability to stimulate DNA repair and protect cells from the 
      environmental hazard paraquat (PQ). PQ-induced mtDNA damage was inversely 
      proportional to the levels of OGG1 expression whereas stimulation of OGG1, in 
      some cases, entirely abolished its cellular effects. The PQ-mediated decline of 
      mitochondrial membrane potential or nuclear condensation were prevented by the 
      OGG1 activators. In addition, in Ogg1(-/-) mouse embryonic fibroblasts 
      complemented with hOGG1(S326C), there was increased cellular and mitochondrial 
      reactive oxygen species compared to their wild type counterparts. Mitochondrial 
      extracts from cells expressing hOGG1(S326C) were deficient in mitochondrial 
      8-oxodG incision activity, which was rescued by the OGG1 activators. These data 
      demonstrate that small molecules can stimulate OGG1 activity with consequent 
      cellular protection. Thus, OGG1-activating compounds may be useful in select 
      humans to mitigate the deleterious effects of environmental oxidants and 
      mutagens.
CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
FAU - Baptiste, Beverly A
AU  - Baptiste BA
AD  - Laboratory of Molecular Gerontology, National Institute on Aging, National 
      Institutes of Health, Baltimore, MD, United States.
FAU - Katchur, Steven R
AU  - Katchur SR
AD  - Respiratory Therapy Area, GSK R&D, Collegeville, PA, United States.
FAU - Fivenson, Elayne M
AU  - Fivenson EM
AD  - Laboratory of Molecular Gerontology, National Institute on Aging, National 
      Institutes of Health, Baltimore, MD, United States.
FAU - Croteau, Deborah L
AU  - Croteau DL
AD  - Laboratory of Molecular Gerontology, National Institute on Aging, National 
      Institutes of Health, Baltimore, MD, United States.
FAU - Rumsey, William L
AU  - Rumsey WL
AD  - Respiratory Therapy Area, GSK R&D, Collegeville, PA, United States.
FAU - Bohr, Vilhelm A
AU  - Bohr VA
AD  - Laboratory of Molecular Gerontology, National Institute on Aging, National 
      Institutes of Health, Baltimore, MD, United States. Electronic address: 
      BohrV@grc.nia.nih.gov.
LA  - eng
GR  - Z01 AG000723-01/ImNIH/Intramural NIH HHS/United States
GR  - Z01 AG000727/ImNIH/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, N.I.H., Intramural
DEP - 20180605
PL  - United States
TA  - Free Radic Biol Med
JT  - Free radical biology & medicine
JID - 8709159
RN  - 0 (DNA, Mitochondrial)
RN  - 0 (Herbicides)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Small Molecule Libraries)
RN  - 452VLY9402 (Serine)
RN  - EC 3.2.2.- (DNA Glycosylases)
RN  - EC 3.2.2.- (Ogg1 protein, mouse)
RN  - EC 3.2.2.- (oxoguanine glycosylase 1, human)
RN  - PLG39H7695 (Paraquat)
SB  - IM
MH  - A549 Cells
MH  - Animals
MH  - Cells, Cultured
MH  - DNA Damage
MH  - DNA Glycosylases/genetics/*metabolism/*physiology
MH  - *DNA Repair
MH  - DNA, Mitochondrial/*genetics
MH  - Fibroblasts/cytology/drug effects/metabolism
MH  - Herbicides/adverse effects
MH  - Humans
MH  - Mice
MH  - Mice, Knockout
MH  - Mitochondria/*drug effects/genetics/metabolism/pathology
MH  - Mutation
MH  - Oxidation-Reduction
MH  - Oxidative Stress/drug effects
MH  - Paraquat/adverse effects
MH  - Reactive Oxygen Species/metabolism
MH  - Serine/genetics/*metabolism
MH  - Small Molecule Libraries/*pharmacology
PMC - PMC6098717
MID - NIHMS975229
OTO - NOTNLM
OT  - 8-Oxoguanine DNA glycosylase-1
OT  - 8-dihydroguanine
OT  - 8-oxo-7
OT  - Base excision repair
OT  - Mitochondria
OT  - OGG1(S326C)
OT  - Oxidative stress
COIS- CONFLICT OF INTEREST The authors state that they have no conflicts of interest to 
      report.
EDAT- 2018/06/08 06:00
MHDA- 2019/10/02 06:00
PMCR- 2019/08/20
CRDT- 2018/06/08 06:00
PHST- 2018/03/28 00:00 [received]
PHST- 2018/05/30 00:00 [revised]
PHST- 2018/05/31 00:00 [accepted]
PHST- 2018/06/08 06:00 [pubmed]
PHST- 2019/10/02 06:00 [medline]
PHST- 2018/06/08 06:00 [entrez]
PHST- 2019/08/20 00:00 [pmc-release]
AID - S0891-5849(18)30975-4 [pii]
AID - 10.1016/j.freeradbiomed.2018.05.094 [doi]
PST - ppublish
SO  - Free Radic Biol Med. 2018 Aug 20;124:149-162. doi: 
      10.1016/j.freeradbiomed.2018.05.094. Epub 2018 Jun 5.