Inhibition of the ATM/p53 Signal Transduction Pathway by Kaposi's Sarcoma-Associated Herpesvirus Interferon Regulatory Factor 1

Abstract

Infected cells recognize viral replication as a DNA damage stress and elicit the ataxia telangiectasia-mutated (ATM)/p53-mediated DNA damage response signal transduction pathway as part of the host surveillance mechanisms, which ultimately induces the irreversible cell cycle arrest and apoptosis. Viruses have evolved a variety of mechanisms to counteract this host intracellular innate immunity. Kaposi's sarcoma-associated herpesvirus (KSHV) viral interferon regulatory factor 1 (vIRF1) interacts with the cellular p53 tumor suppressor through its central DNA binding domain, and this interaction inhibits transcriptional activation of p53. Here, we further demonstrate that KSHV vIRF1 downregulates the total p53 protein level by facilitating its proteasome-mediated degradation. Detailed biochemical study showed that vIRF1 interacted with cellular ATM kinase through its carboxyl-terminal transactivation domain and that this interaction blocked the activation of ATM kinase activity induced by DNA damage stress. As a consequence, vIRF1 expression greatly reduced the level of serine 15 phosphorylation of p53, resulting in an increase of p53 ubiquitination and thereby a decrease of its protein stability. These results indicate that KSHV vIRF1 comprehensively compromises an ATM/p53-mediated DNA damage response checkpoint by targeting both upstream ATM kinase and downstream p53 tumor suppressor, which might circumvent host growth surveillance and facilitate viral replication in infected cells.To prevent the fixation of mutations from one cell generation to the next and also maintain genomic stability, cells have evolved regulatory mechanisms that ensure the order and fidelity of cell cycle events, such as DNA replication and cell division. This regulatory mechanism becomes activated when cells are exposed to genotoxic agents or other adverse environmental conditions such as viral infection (reviewed in reference 38). The ataxia telangiectasia-mutated (ATM) and ataxia telangiectasia-and Rad3-related (ATR) kinases, both of which are phosphoinositide 3-kinase-related kinases, are critical for transducing DNA damage signals to checkpoint control proteins (51). ATM is essential for mediating cell cycle checkpoint control in cells exposed to ionizing radiation and other agents that produce double-strand breaks in DNA (25). In contrast, ATR is activated by stalled replication forks and agents that produce bulky adducts, such as UV irradiation (45). Upon DNA damage signaling, activation of both kinases results in the direct or indirect phosphorylation or activation of a number of downstream checkpoint controls, DNA repair, or apoptosis-promoting targets, including p53, Chk1, and Chk2 (3,8,18,37,53). Chk1 and Chk2 become phosphorylated at serine 345 (34) and threonine 68 (37), respectively, following genotoxic exposure. The roles of Chk1 and Chk2 in response to DNA damage are essential, as inhibition of the ATM/Chk2 pathway results in a loss of the G 2 /M checkpoint and increased sensitivity to ionizing radiation, whereas Chk2 mutat...

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Cellular DNA repair cofactors affecting hepatitis B virus infection and replication

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Kaposi’s sarcoma-associated herpesvirus viral interferon regulatory factor-2 inhibits type 1 interferon signalling by targeting interferon-stimulated gene factor-3

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