. Our findings uncover a direct link between ATM and SV40 LTag that may have implications for understanding the replication cycle of oncogenic polyoma viruses.The eukaryotic DNA damage response represents a series of highly integrated and tightly regulated pathways that coordinate DNA repair, cell cycle, and homeostatic responses to abnormal DNA structures arising endogenously or following exposure to extrinsic genotoxic stimuli. Central to the DNA damage response are a pair of structurally and functionally related protein kinases, designated ATM 2 (ataxia-telangiectasia-mutated) and ATR (ATM-Rad3-related) belonging to the phosphoinositide 3-kinase-related kinase (PIKK) gene superfamily. ATM and ATR share a conserved carboxyl-terminal catalytic domain and display highly overlapping substrate specificities in vitro (1-3). Substrates for ATM and ATR include the p53 and BRCA1 tumor suppressors among many other proteins involved in cell cycle checkpoint activation, DNA repair, and transcriptional regulation (1, 3). Mutations in ATM cause the cancer susceptibility-neurodegeneration syndrome, ataxia-telangiectasia (1, 4). ATM-deficient cells are grossly defective in the ionizing radiation (IR)-induced G 1 /S, intra-S phase, and G 2 /M checkpoints and are profoundly sensitive to IR and other agents that induce DNA double-strand breaks (DSBs) (1). Although structurally and functionally related to ATM, the major functions of ATR pertain to its roles in DNA replication (5). ATR prevents premature firing of DNA replicons, couples the completion of S phase to mitosis, and is required for chromosome maintenance and stabilization of stalled DNA replication forks (6 -10). Although null mutations in ATR are lethal, hypomorphic splicing mutations that reduce ATR protein levels are associated with a rare congenital condition known as Seckel's syndrome (11-13).The catalytic activity of ATM is rapidly up-regulated in response to IR and other DSB-inducing agents. Catalytic activation involves the transautophosphorylation of inactive, dimeric ATM on Ser-1981, followed by dissociation into active monomers (14). The trimeric complex of MRE11, RAD50, and NBS1 (MRN) facilitates ATM activation and ATMdependent substrate phosphorylation through recruitment of ATM to DSBs and/or orientation of the ATM catalytic domain (15-18). Recent studies suggest that the recruitment of ATM is mediated by the carboxyl terminus of NBS1 (19,20). Although ATR isolated from DNA-damaged cells does not show enhanced kinase activity, its recruitment to regions of stalled DNA replication is regulated through binding to the ATRinteracting protein (ATRIP) and replication protein A (RPA) (19,21). Among many key substrates for ATR and ATM are the checkpoint effector kinases, CHK1 and CHK2, which are phosphorylated by ATM and ATR in response to DSBs and DNA replication stress, respectively (6,(22)(23)(24). CHK1 and CHK2 promote checkpoint arrest through phosphorylation and inactivation of CDC25 family phosphatases (25-28).Virus infection can also elicit ATM-dependent...
Lymphoblastic cell lines were infected with simian virus 40 (SV40) and then monitored for evidence of a productive infection. No evidence of early gene expression was found 2 days following infection, as determined by assaying viral mRNAs and early antigens. Furthermore, only small amounts of virus could be detected by plaque assay 2 days after infection, and levels slowly declined until they were undetectable after a few weeks in culture. Thus, human lymphocytes are not readily infectible with SV40 and do not provide a simple model for studying interactions of SV40 with a human cell type.
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