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Journal of Virology, September 2007, p. 9004-9012, Vol. 81, No. 17
0022-538X/07/$08.00+0     doi:10.1128/JVI.02502-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Mn2+ Suppressor Mutations and Biochemical Communication between Ty1 Reverse Transcriptase and RNase H Domains{triangledown}

Robert M. Yarrington, Jichao Chen, Eric C. Bolton,{dagger} and Jef D. Boeke*

Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore Maryland 21205

Received 13 November 2006/ Accepted 23 May 2007

Ty1 reverse transcriptase/RNase H (RT/RH) is exquisitely sensitive to manganese concentrations. Elevated intracellular free Mn2+ inhibits Ty1 retrotransposition and in vitro Ty1 RT-polymerizing activity. Furthermore, Mn2+ inhibition is not limited to the Ty1 RT, as this ion similarly inhibits the activities of both avian myeloblastosis virus and human immunodeficiency virus type 1 RTs. To further characterize Mn2+ inhibition, we generated RT/RH suppressor mutants capable of increased Ty1 transposition in pmr1{Delta} cells. PMR1 codes for a P-type ATPase that regulates intracellular calcium and manganese ion homeostasis, and pmr1 mutants accumulate elevated intracellular manganese levels and display 100-fold less transposition than PMR1+ cells. Mapping of these suppressor mutations revealed, surprisingly, that suppressor point mutations localize not to the RT itself but to the RH domain of the protein. Furthermore, Mn2+ inhibition of in vitro RT activity is greatly reduced in all the suppressor mutants, whereas RH activity and cleavage specificity remain largely unchanged. These intriguing results reveal that the effect of these suppressor mutations is transmitted to the polymerase domain and suggest biochemical communication between these two domains during reverse transcription.

* Corresponding author. Mailing address: Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore MD 21205. Phone: (410) 955-0398. Fax: (410) 614-2987. E-mail: jboeke{at}jhmi.edu

{triangledown} Published ahead of print on 30 May 2007.

{dagger} Present address: Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143.

Journal of Virology, September 2007, p. 9004-9012, Vol. 81, No. 17
0022-538X/07/$08.00+0     doi:10.1128/JVI.02502-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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