AI Article Synopsis
- 7-Methylguanine (7-MG) is a natural compound that inhibits the DNA repair enzyme PARP-1 and shows potential as an anticancer drug.
- The study uses various techniques to explore how 7-MG interacts with PARP-1 and DNA at a molecular level, revealing that it competes with the NAD substrate in the enzyme's active site.
- By binding to PARP-1, 7-MG promotes the formation of complexes with nucleosomes, hindering DNA repair processes and potentially allowing DNA damage to persist.
Article Abstract
7-Methylguanine (7-MG), a natural compound that inhibits DNA repair enzyme poly(ADP-ribose) polymerase 1 (PARP-1), can be considered as a potential anticancer drug candidate. Here we describe a study of 7-MG inhibition mechanism using molecular dynamics, fluorescence anisotropy and single-particle Förster resonance energy transfer (spFRET) microscopy approaches to elucidate intermolecular interactions between 7-MG, PARP-1 and nucleosomal DNA. It is shown that 7-MG competes with substrate NAD and its binding in the PARP-1 active site is mediated by hydrogen bonds and nonpolar interactions with the Gly863, Ala898, Ser904, and Tyr907 residues. 7-MG promotes formation of the PARP-1-nucleosome complexes and suppresses DNA-dependent PARP-1 automodification. This results in nonproductive trapping of PARP-1 on nucleosomes and likely prevents the removal of genotoxic DNA lesions.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139824 | PMC |
| http://dx.doi.org/10.3390/ijms21062159 | DOI Listing |
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