Inhibition of non-homologous end joining of gamma ray-induced DNA double-strand breaks by cAMP signaling in lung cancer cells

• Published in: Scientific reports Vol. 10; no. 1; p. 14455
• Main Authors: Noh, Sung-Eun, Juhnn, Yong-Sung
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.09.2020; Nature Publishing Group
• Subjects: 631/337; 631/45; 631/67; 692/308; 692/4017; 692/4028; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Catalytic Domain - genetics; Cyclic AMP - genetics; Cyclic AMP-Dependent Protein Kinases - genetics; DNA Breaks, Double-Stranded - radiation effects; DNA Damage - radiation effects; DNA End-Joining Repair - genetics; DNA End-Joining Repair - radiation effects; DNA Ligase ATP - genetics; DNA Repair - radiation effects; DNA-Activated Protein Kinase - genetics; DNA-Binding Proteins - genetics; Gamma Rays - adverse effects; Gene expression; Gene Expression Regulation, Neoplastic - radiation effects; Humanities and Social Sciences; Humans; Hypoxia; Lung cancer; MicroRNAs; miRNA; multidisciplinary; Osteoarthritis; Phosphorylation - radiation effects; Rheumatoid arthritis; Science; Science (multidisciplinary); Signal transduction; Signal Transduction - radiation effects; Vitamin B6; Wnt protein
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-71522-9

DNA double-strand breaks (DSB) are formed by various exogenous and endogenous factors and are repaired by homologous recombination and non-homologous end joining (NHEJ). DNA-dependent protein kinase (DNA-PK) is the principal enzyme for NHEJ. We explored the role and the underlying mechanism of cAMP signaling in the NHEJ repair of DSBs resulted from gamma ray irradiation to non-small cell lung cancer (NSLC) cells. Activated cAMP signaling by expression of an activated stimulatory GTP-binding protein or by pretreatment with isoproterenol and prostaglandin E2, delayed the repair of DSBs resulted from gamma ray irradiation, and the delaying effects depended on protein kinase A (PKA). Activated cAMP signaling suppressed XRCC4 and DNA ligase IV recruitment into DSB foci, and reduced phosphorylation at T2609 in DNA-PK catalytic subunit (DNA-PKcs) with a concomitant increase in phosphorylation at S2056 in PKA-dependent ways following gamma ray irradiation. cAMP signaling decreased phosphorylation of T2609 by protein phosphatase 2A-dependent inhibition of ATM. We conclude that cAMP signaling delays the repair of gamma ray-induced DNA DSBs in NSLC cells by inhibiting NHEJ via PKA-dependent pathways, and that cAMP signaling differentially modulates DNA-PKcs phosphorylation at S2056 and T2609, which might contribute to the inhibition of NHEJ in NSLC cells.