title: Caffeine and human DNA metabolism: the magic and the mystery.
abstract: The ability of caffeine to reverse cell cycle checkpoint function and enhance genotoxicity after DNA damage was examined in telomerase-expressing human fibroblasts. Caffeine reversed the ATM-dependent S and G2 checkpoint responses to DNA damage induced by ionizing radiation (IR), as well as the ATR- and Chk1-dependent S checkpoint response to ultraviolet radiation (UVC). Remarkably, under conditions in which IR-induced G2 delay was reversed by caffeine, IR-induced G1 arrest was not. Incubation in caffeine did not increase the percentage of cells entering the S phase 6-8h after irradiation; ATM-dependent phosphorylation of p53 and transactivation of p21(Cip1/Waf1) post-IR were resistant to caffeine. Caffeine alone induced a concentration- and time-dependent inhibition of DNA synthesis. It inhibited the entry of human fibroblasts into S phase by 70-80% regardless of the presence or absence of wildtype ATM or p53. Caffeine also enhanced the inhibition of cell proliferation induced by UVC in XP variant fibroblasts. This effect was reversed by expression of DNA polymerase eta, indicating that translesion synthesis of UVC-induced pyrimidine dimers by DNA pol eta protects human fibroblasts against UVC genotoxic effects even when other DNA repair functions are compromised by caffeine.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. wkarlk@med.unc.edu
authors.forename: William K
authors.initials: WK
authors.lastname: Kaufmann
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Heffernan
authors.forename: Lea M
authors.initials: LM
authors.lastname: Beaulieu
authors.forename: Sharon
authors.initials: S
authors.lastname: Doherty
authors.forename: Alexandra R
authors.initials: AR
authors.lastname: Frank
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Zhou
authors.forename: Miriam F
authors.initials: MF
authors.lastname: Bryant
authors.forename: Tong
authors.initials: T
authors.lastname: Zhou
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Luche
authors.forename: Nana
authors.initials: N
authors.lastname: Nikolaishvili-Feinberg
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Simpson
authors.forename: Marila
authors.initials: M
authors.lastname: Cordeiro-Stone
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D002110:Caffeine / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D018797:Cell Cycle Proteins; D002460:Cell Line; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D000071877:Checkpoint Kinase 1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004247:DNA / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D004268:DNA-Binding Proteins; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D016350:Leucine Zippers; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D014466:Ultraviolet Rays; D000099270:Y-Family DNA Polymerases
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D002110:Caffeine; D018797:Cell Cycle Proteins; D000697:Central Nervous System Stimulants; D000071877:Checkpoint Kinase 1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004247:DNA; D004268:DNA-Binding Proteins; D004259:DNA-Directed DNA Polymerase; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C493956:CDKN1A protein, human; C576324:ATM protein, human; C000605867:CHEK1 protein, human; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases