Crystal structure, biochemical and cellular activities demonstrate separate functions of MTH1 and MTH2
Why is this work in the frame?
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
No Canadian affiliation. An affiliation-only frame — the usual design — would never have seen this work. It is one of the works that make the case for inverting the frame.
The three-model screen
all 1,000 screened works →All three models called this out of scope.
Structural and cellular study separating the functions of MTH1 and MTH2/NUDT15; the object is enzyme biology.
The study investigates molecular functions in cancer biology rather than research itself.
Structural and cellular biochemistry of MTH1/MTH2 enzymes; cancer biology domain research.
Abstract
Deregulated redox metabolism in cancer leads to oxidative damage to cellular components including deoxyribonucleoside triphosphates (dNTPs). Targeting dNTP pool sanitizing enzymes, such as MTH1, is a highly promising anticancer strategy. The MTH2 protein, known as NUDT15, is described as the second human homologue of bacterial MutT with 8-oxo-dGTPase activity. We present the first NUDT15 crystal structure and demonstrate that NUDT15 prefers other nucleotide substrates over 8-oxo-dGTP. Key structural features are identified that explain different substrate preferences for NUDT15 and MTH1. We find that depletion of NUDT15 has no effect on incorporation of 8-oxo-dGTP into DNA and does not impact cancer cell survival in cell lines tested. NUDT17 and NUDT18 were also profiled and found to have far less activity than MTH1 against oxidized nucleotides. We show that NUDT15 is not a biologically relevant 8-oxo-dGTPase, and that MTH1 is the most prominent sanitizer of the cellular dNTP pool known to date.
Stored with the screening record, where it is evidence for the labels above.
The record
- Venue
- Nature Communications
- Topic
- DNA Repair Mechanisms
- Field
- Biochemistry, Genetics and Molecular Biology
- Canadian institutions
- —
- Funders
- Canadian Institutes of Health ResearchVetenskapsrådetKnut och Alice Wallenbergs StiftelseCancerfondenEuropean Synchrotron Radiation FacilityWenner-Gren Stiftelserna
- Keywords
- NucleotideBiochemistryDNAEnzymeOxidative phosphorylationChemistryHEK 293 cellsSubstrate (aquarium)Cell cultureBiologyCell biologyGeneGenetics
- Has abstract in OpenAlex
- yes