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Journal of Virology, July 2008, p. 6952-6961, Vol. 82, No. 14
0022-538X/08/$08.00+0     doi:10.1128/JVI.02331-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Human T-Cell Leukemia Virus Type 1 Tax Attenuates the ATM-Mediated Cellular DNA Damage Response{triangledown}

Chandtip Chandhasin ,1,{dagger},{ddagger} Razvan I. Ducu,1,{dagger} Elijahu Berkovich,2 Michael B. Kastan,2 and Susan J. Marriott1*

Department of Molecular Virology and Microbiology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030,1 Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 381052

Received 27 October 2007/ Accepted 14 April 2008

Genomic instability, a hallmark of leukemic cells, is associated with malfunctioning cellular responses to DNA damage caused by defective cell cycle checkpoints and/or DNA repair. Adult T-cell leukemia, which can result from infection with human T-cell leukemia virus type 1 (HTLV-1), is associated with extensive genomic instability that has been attributed to the viral oncoprotein Tax. How Tax influences cellular responses to DNA damage to mediate genomic instability, however, remains unclear. Therefore, we investigated the effect of Tax on cellular pathways involved in recognition and repair of DNA double-strand breaks. Premature attenuation of ATM kinase activity and reduced association of MDC1 with repair foci were observed in Tax-expressing cells. Following ionizing radiation-induced S-phase checkpoint activation, Tax-expressing cells progressed more rapidly than non-Tax-expressing cells toward DNA replication. These results demonstrate that Tax expression may allow premature DNA replication in the presence of genomic lesions. Attempts to replicate in the presence of these lesions would result in gradual accumulation of mutations, leading to genome instability and cellular transformation.

* Corresponding author. Mailing address: Department of Molecular Virology and Microbiology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Phone: (713) 798-4440. Fax: (713) 798-4435. E-mail: susanm{at}bcm.edu

{triangledown} Published ahead of print on 23 April 2008.

{dagger} C.C. and R.I.D. contributed equally to the work.

{ddagger} Present address: Department of Investigational Cancer Therapeutics, M.D. Anderson Cancer Center, 1515 Holcombe Blvd. Unit 455, Houston, TX 77030.

Journal of Virology, July 2008, p. 6952-6961, Vol. 82, No. 14
0022-538X/08/$08.00+0     doi:10.1128/JVI.02331-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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