Slow repair of lipid peroxidation-induced DNA damage at p53 mutation hotspots in human cells caused by low turnover of a DNA glycosylase. Issue 14 (31st July 2014)

• Record Type: Journal Article
• Authors: Woodrick, Jordan; Gupta, Suhani; Khatkar, Pooja; Sarangi, Sanchita; Narasimhan, Ganga; Trehan, Akriti; Adhikari, Sanjay; Roy, Rabindra
• Is Part Of: Nucleic acids research. Volume 42:Issue 14(2014)
• Page Start: 9033
• Page End: 9046
• Publication Date: 2014-07-31
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gku520
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: Repair of oxidative stress- and inflammation-induced DNA lesions by the base excision repair (BER) pathway prevents mutation, a form of genomic instability which is often observed in cancer as 'mutation hotspots'. This suggests that some sequences have inherent mutability, possibly due to sequence-related differences in repair. This study has explored intrinsic mutability as a consequence of sequence-specific repair of lipid peroxidation-induced DNA adduct, 1, N 6 -ethenoadenine (εA). For the first time, we observed significant delay in repair of ϵA at mutation hotspots in the tumor suppressor gene p53 compared to non-hotspots in live human hepatocytes and endothelial cells using an in-cell real time PCR-based method. In-cell and in vitro mechanism studies revealed that this delay in repair was due to inefficient turnover of N -methylpurine-DNA glycosylase (MPG), which initiates BER of εA. We determined that the product dissociation rate of MPG at the hotspot codons was ≈5–12-fold lower than the non-hotspots, suggesting a previously unknown mechanism for slower repair at mutation hotspots and implicating sequence-related variability of DNA repair efficiency to be responsible for mutation hotspot signatures.