title: Tousled kinase activator, gallic acid, promotes homologous recombinational repair and suppresses radiation cytotoxicity in salivary gland cells.
abstract: Accidental or medical radiation exposure of the salivary glands can gravely impact oral health. Previous studies have shown the importance of Tousled-like kinase 1 (TLK1) and its alternate start variant TLK1B in cell survival against genotoxic stresses. Through a high-throughput library screening of natural compounds, the phenolic phytochemical, gallic acid (GA), was identified as a modulator of TLK1/1B. This small molecule possesses anti-oxidant and free radical scavenging properties, but in this study, we report that in vitro it promotes survival of human salivary acinar cells, NS-SV-AC, through repair of ionizing radiation damage. Irradiated cells treated with GA show improved clonogenic survival compared to untreated controls. And, analyses of DNA repair kinetics by alkaline single-cell gel electrophoresis and γ-H2AX foci immunofluorescence indicate rapid resolution of DNA breaks in drug-treated cells. Study of DR-GFP transgene repair indicates GA facilitates homologous recombinational repair to establish a functional GFP gene. In contrast, inactivation of TLK1 or its shRNA knockdown suppressed resolution of radiation-induced DNA tails in NS-SV-AC, and homology directed repair in DR-GFP cells. Consistent with our results in culture, animals treated with GA after exposure to fractionated radiation showed better preservation of salivary function compared to saline-treated animals. Our results suggest that GA-mediated transient modulation of TLK1 activity promotes DNA repair and suppresses radiation cytoxicity in salivary gland cells.
authors: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA.
authors: Prakash Srinivasan
authors: PS
authors: Timiri Shanmugam
authors: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA.
authors: Renjith Parameshwaran
authors: RP
authors: Nair
authors: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA.
authors: Arrigo
authors: A
authors: De Benedetti
authors: Department of Computational Biology and Bioinformatics, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA.
authors: Gloria
authors: G
authors: Caldito
authors: Department of Pathology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA.
authors: Fleurette
authors: F
authors: Abreo
authors: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA. Electronic address: gsunav@lsuhsc.edu.
authors: Gulshan
authors: G
authors: Sunavala-Dossabhoy
mesh_terms: D000975:Antioxidants; D002460:Cell Line; D004260:DNA Repair / Q000187:drug effects; D005707:Gallic Acid / Q000008:administration & dosage*; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D011839:Radiation, Ionizing; D011837:Radiation-Protective Agents / Q000008:administration & dosage; D059767:Recombinational DNA Repair / Q000187:drug effects* / Q000235:genetics; D012469:Salivary Glands / Q000187:drug effects* / Q000528:radiation effects
chemical_list: D000975:Antioxidants; D011837:Radiation-Protective Agents; D005707:Gallic Acid; D017346:Protein Serine-Threonine Kinases; C425323:TLK1 protein, human
keywords: Acinar; DNA repair; Gallic acid; Homologous recombination; Radiation; Salivary; Tousled; Xerostomia