Professor Stephen P. Goff Phone: 212-305-3794 Lab Phone: 212-305-7956 Fax: 212-305-5106 Email: spg1@columbia.edu Website: microbiology.columbia.edu/goff-lab-home

Professor Stephen P. Goff
Phone: 212-305-3794
Lab Phone: 212-305-7956
Fax: 212-305-5106
Email: spg1@columbia.edu
Website: microbiology.columbia.edu/goff-lab-home

Stephen P. Goff, Ph.D.

Higgins Professor of Microbiology & Immunology and Biochemistry & Molecular Biophysics
Member, National Academy of Sciences
Member, National Academy of Medicine
Member, American Academy of Arts & Sciences
Fellow, American Association for the Advancement of Science
Ph.D., Stanford University

Molecular biology of retrovirus replication; host restriction factors; endogenous retroviruses and transposable elements

Research
The central effort of our laboratory for several years has been a detailed genetic analysis of the replication cycle of the Moloney murine leukemia virus (M-MuLV) and the human immunodeficiency virus type 1 (HIV-1). The major approach has been to create mutations in cloned DNA copies of the viral genomes and to determine the effect of the mutations on the viral life cycle after transfer of the altered DNAs into cells in culture. These genetic analyses have defined the functional domains of various viral proteins and the sites of their action on viral nucleic acids. We have also expressed reverse transcriptase and integrase in bacteria and studied these enzymes biochemically. We make use of the yeast two-hybrid system to monitor protein-protein interactions between viral proteins, and to identify new host proteins that interact with the Gag, Pol and Env gene products. Finally, we use genetic selections in mammalian cells to screen overexpression libraries and gene knock-down libraries to identify genes that restrict virus replication or, alternatively, are essential for virus replication, especially those affecting intracellular trafficking of the viruses. Our work also addresses the control of retroviral gene expression in embryonic stem cells. Recently we have begun charactering a retroviral element associated with a leukemia-like disease in the mollusk Mya arenaria, the soft-shell clam.

Please see our lab website for more information about our members and research.

 

Selected Publications

  1. Li, Z., Duan, S., Hua, X., Xu, X., Li, Y., Menolfi, D., Zhou, H., Lu, C., Zha, S., Goff, S.P. and Zhang, Z. (2023) Asymmetric distribution of parental H3K9me3 in S phase silences L1 elements. Nature 623: 643–651. https://doi.org/10.1038/s41586-023-06711-3

  2. Hart, S.F.M., Yonemitsu, M.A., Giersch, R.M., Garrett, F.E.S., Beal, B.F., Arriagada, G., Davis, B.W., Ostrander, E.A., Goff, S.P. and Metzger, M.J. (2023). Centuries of genome instability and evolution in soft-shell clam, Mya arenaria, bivalve transmissible neoplasia. Nature Cancer 4: 1561–1574. https://doi.org/10.1038/s43018-023-00643-7

  3. Duan, Y., Zhou, H., Liu, X., Iketani, S., Lin, M., Zhang, X., Bian, Q., Wang, H., Sun, H., Hong, S.J., Culbertson, B., Mohri, H., Luck, M.I., Zhu, Y., Liu, X., Lu, Y., Yang, X., Yang, K., Sabo, Y., Chavez, A., Goff, S.P., Rao, Z., Ho, D.D., and Yang, H. (2023). Molecular mechanisms of SARS-CoV-2 resistance to nirmatrelvir. Nature 622: 376–382. https://doi.org/10.1038/s41586-023-06609-0

  4. Iketani, S., Mohri, H., Culbertson, B., Hong, S.J., Duan, Y., Luck, M.I., Annavajhala, M.K., Guo, Y., Sheng, Z., Uhlemann, A.C., Goff, S.P., Sabo, Y., Yang, H., Chavez, A., and Ho, D.D. (2023). Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir. Nature 613: 558–564. https://doi.org/10.1038/s41586-022-05514-2

  5. Winans, S., Yu, H. J., de los Santos, K., Wang, G.Z., KewalRamani, V.N. and Goff, S.P. (2022) A point mutation in HIV-1 integrase redirects proviral integration into centromeric repeats. Nature Commun. 13: 1474.

  6. Geis, F.K., Sabo, Y., Chen, X., Li, Y., Lu, C. and Goff, S.P. (2022) CHAF1A/B mediate silencing of unintegrated HIV-1 DNAs early in infection. Proc. Natl. Acad. Sci. U.S.A. 119: e2116735119.

  7. Wang, G.Z. and Goff, S.P. (2021) Moloney murine leukemia virus p12 is required for histone loading onto retroviral DNAs. J. Virol. 95: e0049521.

  8. Winans, S. and Goff, S.P. (2020) Mutations altering acetylated residues in the CTD of HIV-1 integrase cause defects in proviral transcription at early times after integration of viral DNA. PLoS Pathog. 16: e1009147.

  9. Wang, G.Z. and Goff, S.P. (2020) Yin Yang 1 is a potent activator of human T lymphotropic virus type 1 LTR-driven gene expression via RNA binding. Proc. Natl. Acad. Sci. U.S.A. 117: 18701-18710. https://pubmed.ncbi.nlm.nih.gov/32690679/

  10. Sabo, Y., de Los Santos, K. and Goff, S.P. (2020) IQGAP1 negatively regulates HIV-1 Gag trafficking and virion production. Cell Rep. 30: 4065-4081.e4.

  11. Geis, F.K. and Goff, S.P. (2019) Unintegrated HIV-1 DNAs are loaded with core and linker histones and transcriptionally silenced. Proc. Natl. Acad. Sci. U.S.A. 116: 23735-23742.

  12. Zhu, Y., Wang, G.Z., Cingoz, O. and Goff, S.P. (2018) NP220 mediates silencing of unintegrated retroviral DNA. Nature 564:278-282.

  13. Metzger, M.J., Paynter, A.N., Siddall, M.E. and Goff, S.P. (2018) Horizontal transfer of retrotransposons between bivalves and other aquatic species of multiple phyla. Proc. Natl. Acad. Sci. U.S.A. 115:E4227-E4235.

  14. Cingoz, O. and Goff, S.P. (2018) Cyclin-dependent kinase activity is required for type I interferon production. Proc. Natl. Acad. Sci. U.S.A. 115:E2950-E2959.

  15. Lee, A., Cingoz, O., Sabo, Y. and Goff, S.P. (2018) Characterization of interaction between Trim28 and YY1 in silencing proviral DNA of Moloney murine leukemia virus. Virology 516:165-175.

  16. Zhu, Y., Luo, S., Sabo, Y., Wang, C., Tong, L. and Goff, S.P. (2017) Heme oxygenase 2 binds myristate to regulate retrovirus assembly and TLR4 signaling. Cell Host Microbe 21: 220-230.

  17. Wang, C. and Goff, S.P. (2017) Differential control of retrovirus silencing in embryonic cells by proteasomal regulation of the ZFP809 retroviral repressor. Proc. Natl. Acad. Sci. U.S.A. 114:E922-E930.

  18. Wang, G.Z., Wang, Y. and Goff, S.P. (2016) Histones are rapidly loaded onto unintegrated retroviral DNAs soon after nuclear entry. Cell Host Microbe 20: 798-809.

  19. Metzger, M.J., Villalba, A., Carballal, M.J., Iglesias, D., Sherry, J., Reinisch, C., Muttray, A.F., Baldwin, S.A. and Goff, S.P. (2016) Widespread transmission of independent cancer lineages within multiple bivalve species. Nature 534: 705-709.

  20. Green, L. and Goff, S.P. (2015) Translational readthrough-promoting drugs enhance pseudoknot-mediated suppression of the stop codon at the Moloney murine leukemia virus gag-pol junction. J. Gen. Virol. 96: 3411-3421.

  21. Wang, G.Z. and Goff, S.P. (2015) Regulation of Yin Yang 1 by tyrosine phosphorylation. J. Biol. Chem. 290: 21890-21900.

  22. Erazo, A. and Goff, S.P. (2015) Nuclear matrix protein Matrin 3 is a regulator of ZAP-mediated retroviral restriction. Retrovirology 12: 57.

  23. Griffin, D.O. and Goff, S.P. (2015) HIV-1 is restricted prior to integration of viral DNA in primary cord-derived human CD34+ cells. J. Virol. 89: 8096-8100.

  24. Metzger, MJ., Reinisch, C., Sherry, J., and Goff, S.P. (2015) Horizontal transmission of clonal cancer cells causes leukemia in soft-shell clams. Cell 161: 255-263.

  25. Wang, G.Z., and Goff, S.P. (2015) Postentry restriction of Mason-Pfizer monkey virus in mouse cells. J. Virol. 89: 2813-2819.

  26. Arriagada, G., Metzger, M.J., Muttray, A., Sherry, J., Reinisch, C., Street, C., Lipkin, W.I., and Goff, S.P. (2014) Activation of transcription and retrotransposition of a novel retroelement, Steamer, in neoplastic hemocytes of the mollusk Mya arenaria. Proc. Natl. Acad. Sci. U.S.A.111:14175-14180.

  27. Schlesinger, S., Meshorer, E. and Goff, S.P. (2014) Asynchronous transcriptional silencing of individual retroviral genomes in embryonic cells. Retrovirology 11: e31.

  28. Goff, S.P. (2013) HIV: Slipping under the radar. Nature News and Views 503: 352-353.

  29. Schlesinger, S., Lee, A., Wang, G.Z., Green, L. and Goff, S.P. (2013) Proviral silencing in embryonic cells is regulated by Yin Yang 1. Cell Rep. 4: 1-9.

  30. Schlesinger, S. and Goff, S.P. (2013) Silencing of proviruses in embryonic cells: Efficiency, stability, and chromatin modifications. EMBO Rep. 14: 73-79.

  31. Hogg, J.R. and Goff, S.P. (2010) Upf1 senses 3' UTR length to potentiate mRNA decay. Cell143: 379-389.

  32. Valente, S.T., Gilmartin, G.M., Venkataraman, K. and Goff, S.P. (2009) HIV-1 mRNA 3' end processing is distinctively regulated by eIF3f, CDK11, and splice factor 9G8. Mol. Cell 36:279-289.

  33. Wolf, D. and Goff, S.P. Embryonic stem cells use ZFP809 to silence retroviral DNAs. (2009) Nature 458: 1201-1204.

  34. Wolf, D. and Goff, S.P. (2007) TRIM28 mediates primer binding site-targeted silencing of murine leukemia virus in embryonic cells. Cell 131: 46-57.

  35. Cang, Y., Zhang, J., Nicholas, S.A., Bastien, J., Li, B., Zhou, P. and Goff, S.P. (2006) Deletion of DDB1 in mouse brain and lens leads to p53-dependent elimination of proliferating cells. Cell127: 929-940.

  36. Naghavi, M.H., Hatziioannou, T., Gao, G. and Goff S.P. (2005) Overexpression of fasciculation and elongation protein zeta-1 (FEZ1) induces a post-entry block to retroviruses in cultured cells. Genes Dev. 19: 1105-1115.

  37. Orlova, M., Yueh, A., Leung, J. and Goff, S.P. (2003) Reverse transcriptase of Moloney murine leukemia virus binds to eukaryotic release factor 1 to modulate suppression of translational termination. Cell 115: 319-331.

  38. Gao, G., Guo, X. and Goff, S.P. (2002) Inhibition of retroviral RNA production by ZAP, a novel CCCH-type zinc finger protein. Science 297: 1703-1706.

  39. Tachedjian, G., Orlova, M., Sarafianos, S., Arnold, E. and Goff, S.P. (2001) Nonnucleoside reverse transcriptase inhibitors are chemical enhancers of dimerization of the HIV type1 reverse transcriptase. Proc. Natl. Acad. Sci. U.S.A. 98: 7188-7193.