Translesion Synthesis Past Acrolein-derived DNA Adducts by Human Mitochondrial DNA Polymerase γ

Abstract

Background: Mitochondria lack specialized DNA polymerases that in the nucleus can bypass acrolein-induced DNA adducts. Results: Human mitochondrial DNA polymerase ␥ replicated past acrolein-induced deoxyguanosine adducts inefficiently and in an extremely error-prone manner. Conclusion: Acrolein-induced deoxyguanosine adducts may inhibit replication and cause mutations in mitochondria. Significance: The data suggest a role for pol ␥ in acrolein-induced mitochondrial DNA damage and mutagenesis.

Mitochondrial DNA damage induced autophagy cell death and disease

“…The sole replicative mtDNA polymerase, DNA Pol γ, appears to have very little translesion synthesis capacity; photodimers and bulky lesions are powerful blocks to mtDNA replication in vitro (35–37). There is also strong biochemical evidence that similar forms of damage inhibit transcription by the mitochondrial RNA polymerase (30, 38).…”

“…There is biochemical evidence that photodimers, metabolites of the air pollution constituent benzo(a)pyrene, and acrolein may all result in mtDNA mutations (35–37). This is important because mtDNA mutations cause approximately 200 known diseases affecting at least 1/10,000 people (49, 50), but the origin of those mutations is not understood.…”

Mitochondrial toxicity of tobacco smoke and air pollution

“…Other effects of tobacco cigarette smoke include changes in mitochondrial morphology 19, 37, 38 promoting mitophagy in both cell culture and animal models 37 , the formation of mtDNA adducts 94 , increased mtDNA damage 34 and alterations in mtDNA copy number 35 . Acrolein, one of the primary reactive aldehydes within tobacco cigarette smoke, forms bulky DNA adducts which are likely to persist in the mtDNA due to the inefficiency of the mitochondrial DNA polymerase ɣ resulting in transversions 94 .…”

“…Acrolein, one of the primary reactive aldehydes within tobacco cigarette smoke, forms bulky DNA adducts which are likely to persist in the mtDNA due to the inefficiency of the mitochondrial DNA polymerase ɣ resulting in transversions 94 . However, whether acrolein is one of the primary drivers of mtDNA damage following tobacco smoke exposure has yet to be determined.…”

Analysis of Translesion DNA Synthesis by the Mitochondrial DNA Polymerase γ

“…Translesion DNA synthesis by the human DNA pol γ has been studied for a number of DNA lesions, including 7,8-dihydro-8-oxo-2'-deoxyguanosine (16), benzopyrene adducts (17), UV photoadducts (18), acrolein adducts (19), and several others that are reviewed in (2). We evaluate translesion DNA synthesis by pol γ with synthetic oligonucleotide substrates that contain specific lesions of interest.…”