Nutrient deprivation regulates DNA damage repair in cardiomyocytes via loss of the base-excision repair enzyme OGG1.
Oxidative stress contributes to the pathogenesis of many diseases, including heart failure, but the role and regulation of oxidative DNA damage in many cases have not been studied. Here, we set out to examine how oxidative DNA damage is regulated in cardiomyocytes. Compared to normal healthy controls, human hearts in end-stage cardiomyopathy (EsCM) showed a high degree of DNA damage by histological evidence of damage markers, including 8-oxoG and γH2AX (8-oxoG: 4.7±0.88 vs. 99.9±0.11%; γH2AX: 2.1±0.33 vs. 85.0±13.8%; P<0.01) This raised the possibility that defective DNA repair may be partly responsible. Indeed, nutrient deprivation led to impaired base-excision repair (BER) in cardiomyocytes in vitro, accompanied by loss of the BER enzyme OGG1, while BER activity was rescued by recombinant OGG1 (control vs. nutrient deprived vs. nutrient deprived+OGG1; 100±2.96 vs. 68.2±7.53 vs. 94.0±0.72%; ANOVA, P<0.01). Hearts from humans with EsCM and two murine models of myocardial stress also showed a loss of OGG1 protein. OGG1 loss was inhibited by the autophagy inhibitor bafilomycin and in autophagy-deficient Atg5(-/-) mouse embryonic fibroblasts. However, pharmacological activation of autophagy, itself, did not induce OGG1 loss, suggesting that autophagy is necessary but not sufficient for OGG1 turnover, and OGG1 loss requires concurrent nutrient deprivation. Finally, we found that the role of autophagy in nutrient starvation is complex, since it balanced the positive effects of ROS inhibition against the negative effect of OGG1 loss. Therefore, we have identified a central role for OGG1 in regulating DNA repair in cardiomyopathy. The manipulation of OGG1 may be used in future studies to examine the direct contribution of oxidative DNA damage to the progression of heart failure.
Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Centre of Clinical Investigation Building, Level 6, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
Lee
L
Siggens
Nichola
N
Figg
Martin
M
Bennett
Roger
R
Foo
D000818:Animals; D001483:Base Sequence; D004249:DNA Damage; D045647:DNA Glycosylases / Q000378:metabolism*; D017931:DNA Primers; D004260:DNA Repair; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*
D017931:DNA Primers; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human