STAT3 interrupts ATR-Chk1 signaling to allow oncovirus-mediated cell proliferation
DNA damage response (DDR) is a signaling network that senses DNA damage and activates response pathways to coordinate cell cycle progression and DNA repair. Thus, DDR is critical for maintenance of genome stability, and presents a powerful defense against tumorigenesis. Therefore, to drive cell-proliferation and transformation, viral and cellular oncogenes need to circumvent DDR-induced cell-cycle checkpoints. Unlike in hereditary cancers, mechanisms that attenuate DDR and disrupt cell-cycle checkpoints in sporadic cancers are not well-understood. Using Epstein-Barr virus (EBV) as a source of oncogenes, we have previously shown that EBV-driven cell proliferation requires the cellular transcription factor STAT3. EBV infection is rapidly followed by activation and increased expression of STAT3, which mediates relaxation of the intra-S phase cell-cycle checkpoint; this facilitates viral oncogenedriven cell proliferation. We now show that replication stress-associated DNA damage which results from EBV infection, is detected by DDR. However, signaling downstream of ATR is impaired by STAT3, leading to relaxation of the intra-S phase checkpoint. We find that STAT3 interrupts ATR-to-Chk1 signaling by promoting loss of Claspin, a protein that assists ATR to phosphorylate Chk1. This loss of Claspin which ultimately facilitates cell proliferation is mediated by caspase 7, a protein that typically promotes cell death. Our findings demonstrate how STAT3, which is constitutively active in many human cancers, suppresses DDR, fundamental to tumorigenesis. This newly recognized role for STAT3 in regulation of DDR, discovered in the context of EBV-infection, is of broad interest as the biology of cell proliferation is central to both health and disease.
|Authors||Koganti S, Hui-Yuen J. McAllister S, Gardner B, Grasser F, Palendira U, Tangye SG, Freeman AF and Bhaduri-McIntosh S.|
|Publisher Name||P NATL ACAD SCI USA|
|Published Date||2014-04-01 00:00:00|