Small-molecule activation of OGG1 increases oxidative DNA damage repair by gaining a new function

• Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed b,d-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and aging. © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Ämnesord

TEKNIK OCH TEKNOLOGIER  -- Kemiteknik (hsv//swe)

ENGINEERING AND TECHNOLOGY  -- Chemical Engineering (hsv//eng)

NATURVETENSKAP  -- Kemi (hsv//swe)

NATURAL SCIENCES  -- Chemical Sciences (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

Nyckelord

8 oxoguanine DNA glycosylase 1

DNA glycosyltransferase

glycine

phenylalanine

polynucleotide kinase phosphatase 1

small molecule transport agent

th 1078

unclassified drug

DNA (apurinic or apyrimidinic site) lyase

activation energy

amino acid

catalysis

catalyst

cell

DNA

enzyme activity

nitrogen

phosphatase

aging

Article

controlled study

DNA repair

drug structure

enzyme active site

human

in vitro study

DNA damage

enzyme specificity

metabolism

oxidative stress

DNA Glycosylases

DNA-(Apurinic or Apyrimidinic Site) Lyase

Substrate Specificity

8 oxoguanine DNA glycosylase 1

DNA glycosyltransferase

glycine

phenylalanine

polynucleotide kinase phosphatase 1

small molecule transport agent

th 1078

unclassified drug

DNA (apurinic or apyrimidinic site) lyase

activation energy

amino acid

catalysis

catalyst

cell

DNA

enzyme activity

nitrogen

phosphatase

aging

Article

controlled study

DNA repair

drug structure

enzyme active site

human

in vitro study

DNA damage

enzyme specificity

metabolism

oxidative stress

DNA Damage

DNA Glycosylases

DNA Repair

DNA-(Apurinic or Apyrimidinic Site) Lyase

Oxidative Stress

Substrate Specificity

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)