Activation of Ataxia Telangiectasia-mutated DNA Damage Checkpoint Signal Transduction Elicited by Herpes Simplex Virus Infection

Abstract

Eukaryotic cells are equipped with machinery to monitor and repair damaged DNA. Herpes simplex virus (HSV) DNA replication occurs at discrete sites in nuclei, the replication compartment, where viral replication proteins cluster and synthesize a large amount of viral DNA. In the present study, HSV infection was found to elicit a cellular DNA damage response, with activation of the ataxia-telangiectasia-mutated (ATM) signal transduction pathway, as observed by autophosphorylation of ATM and phosphorylation of multiple downstream targets including Nbs1, Chk2, and p53, while infection with a UV-inactivated virus or with a replication-defective virus did not. Activated ATM and the DNA damage sensor MRN complex composed of Mre11, Rad50, and Nbs1 were recruited and retained at sites of viral DNA replication, probably recognizing newly synthesized viral DNAs as abnormal DNA structures. These events were not observed in ATM-deficient cells, indicating ATM dependence. In Nbs1-deficient cells, HSV infection induced an ATM DNA damage response that was delayed, suggesting a functional MRN complex requirement for efficient ATM activation. However, ATM silencing had no effect on viral replication in 293T cells. Our data open up an interesting question of how the virus is able to complete its replication, although host cells activate ATM checkpoint signaling in response to the HSV infection.

8-60hIPP5m-Induced G2/M Cell Cycle Arrest Involves Activation of ATM/p53/p21cip1/waf1Pathways and Delayed Cyclin B1 Nuclear Translocation

“…This is consistent with the known phenomenon that p53 Ser15 phosphorylation is dependent on ATM (Lavin and Kozlov, 2007). Phosphorylation of p53 results in the stabilization and accumulation of this protein (Shirata et al, 2005), which is important for its role in regulating downstream targets such as p21 cip1/waf1 .…”

Phosphorylation of Sp1 in Response to DNA Damage by Ataxia Telangiectasia-Mutated Kinase

“…Studies comparing the expression of the insulin growth factor receptor-I in normal fibroblasts and AT-mutated fibroblasts showed decreased levels of insulin growth factor-I receptor in ATmutated cells and identified Sp1 as a potential mediator between ATM and insulin growth factor-I receptor expression (38). In addition, ATM is induced by infection of cells with herpes simplex virus-1 and SV40 (71,72), which also induce Sp1 phosphorylation (11,20). Kim and DeLuca have shown that phosphorylated Sp1 purified from herpes simplex virus-1 -infected cells has decreased ability to activate transcription in in vitro transcription assays and that the kinetics of the phosphorylation correlate with the expression of Sp1-independent viral late genes, suggesting a viral-mediated temporal regulation of gene expression.…”

Activation and regulation of ATM kinase activity in response to DNA double-strand breaks

“…Recently, infection of cells with herpes simplex virus (HSV) was also shown to induce an ATM-and MRN-dependent DNA-damage response, including ATM autophosphorylation and phosphorylation of ATM target substrates. Phosphorylation of Nbs1, p53 and Chk2 were not observed in A-T cells and were delayed in NBS cells, suggesting that a functional MRN complex is required for efficient ATM activation (Shirata et al, 2005).…”