PARP1 Inhibition Augments UVB-Mediated Mitochondrial Changes-Implications for UV-Induced DNA Repair and Photocarcinogenesis.
DNA repair
PARP
UVB
autophagy
biogenesis
carcinogenesis
metabolism
mitochondria
Journal
Cancers
ISSN: 2072-6694
Titre abrégé: Cancers (Basel)
Pays: Switzerland
ID NLM: 101526829
Informations de publication
Date de publication:
18 Dec 2019
18 Dec 2019
Historique:
received:
26
11
2019
revised:
07
12
2019
accepted:
10
12
2019
entrez:
22
12
2019
pubmed:
22
12
2019
medline:
22
12
2019
Statut:
epublish
Résumé
Keratinocytes provide the first line of defense of the human body against carcinogenic ultraviolet (UV) radiation. Acute and chronic UVB-mediated cellular responses were widely studied. However, little is known about the role of mitochondrial regulation in UVB-induced DNA damage. Here, we show that poly (ADP-ribose) polymerase 1 (PARP1) and ataxia-telangiectasia-mutated (ATM) kinase, two tumor suppressors, are important regulators in mitochondrial alterations induced by UVB. Our study demonstrates that PARP inhibition by ABT-888 upon UVB treatment exacerbated cyclobutane pyrimidine dimers (CPD) accumulation, cell cycle block and cell death and reduced cell proliferation in premalignant skin keratinocytes. Furthermore, in human keratinocytes UVB enhanced oxidative phosphorylation (OXPHOS) and autophagy which were further induced upon PARP inhibition. Immunoblot analysis showed that these cellular responses to PARP inhibition upon UVB irradiation strongly alter the phosphorylation level of ATM, adenosine monophosphate-activated kinase (AMPK), p53, protein kinase B (AKT), and mammalian target of rapamycin (mTOR) proteins. Furthermore, chemical inhibition of ATM led to significant reduction in AMPK, p53, AKT, and mTOR activation suggesting the central role of ATM in the UVB-mediated mitochondrial changes. Our results suggest a possible link between UVB-induced DNA damage and metabolic adaptations of mitochondria and reveal the OXPHOS-regulating role of autophagy which is dependent on key metabolic and DNA damage regulators downstream of PARP1 and ATM.
Identifiants
pubmed: 31861350
pii: cancers12010005
doi: 10.3390/cancers12010005
pmc: PMC7016756
pii:
doi:
Types de publication
Journal Article
Langues
eng
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