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Retroviral DNA Integration: Viral and Cellular Determinants of Target-Site Selection

Retroviruses differ in their preferences for sites for viral DNA integration in the chromosomes of infected cells. Human immunodeficiency virus (HIV) integrates preferentially within active transcription units, whereas murine leukemia virus (MLV) integrates preferentially near transcription start si...

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Autores principales: Lewinski, Mary K, Yamashita, Masahiro, Emerman, Michael, Ciuffi, Angela, Marshall, Heather, Crawford, Gregory, Collins, Francis, Shinn, Paul, Leipzig, Jeremy, Hannenhalli, Sridhar, Berry, Charles C, Ecker, Joseph R, Bushman, Frederic D
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2006
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1480600/
https://www.ncbi.nlm.nih.gov/pubmed/16789841
http://dx.doi.org/10.1371/journal.ppat.0020060
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author Lewinski, Mary K
Yamashita, Masahiro
Emerman, Michael
Ciuffi, Angela
Marshall, Heather
Crawford, Gregory
Collins, Francis
Shinn, Paul
Leipzig, Jeremy
Hannenhalli, Sridhar
Berry, Charles C
Ecker, Joseph R
Bushman, Frederic D
author_facet Lewinski, Mary K
Yamashita, Masahiro
Emerman, Michael
Ciuffi, Angela
Marshall, Heather
Crawford, Gregory
Collins, Francis
Shinn, Paul
Leipzig, Jeremy
Hannenhalli, Sridhar
Berry, Charles C
Ecker, Joseph R
Bushman, Frederic D
author_sort Lewinski, Mary K
collection PubMed
description Retroviruses differ in their preferences for sites for viral DNA integration in the chromosomes of infected cells. Human immunodeficiency virus (HIV) integrates preferentially within active transcription units, whereas murine leukemia virus (MLV) integrates preferentially near transcription start sites and CpG islands. We investigated the viral determinants of integration-site selection using HIV chimeras with MLV genes substituted for their HIV counterparts. We found that transferring the MLV integrase (IN) coding region into HIV (to make HIVmIN) caused the hybrid to integrate with a specificity close to that of MLV. Addition of MLV gag (to make HIVmGagmIN) further increased the similarity of target-site selection to that of MLV. A chimeric virus with MLV Gag only (HIVmGag) displayed targeting preferences different from that of both HIV and MLV, further implicating Gag proteins in targeting as well as IN. We also report a genome-wide analysis indicating that MLV, but not HIV, favors integration near DNase I–hypersensitive sites (i.e., +/− 1 kb), and that HIVmIN and HIVmGagmIN also favored integration near these features. These findings reveal that IN is the principal viral determinant of integration specificity; they also reveal a new role for Gag-derived proteins, and strengthen models for integration targeting based on tethering of viral IN proteins to host proteins.
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spelling pubmed-14806002006-06-23 Retroviral DNA Integration: Viral and Cellular Determinants of Target-Site Selection Lewinski, Mary K Yamashita, Masahiro Emerman, Michael Ciuffi, Angela Marshall, Heather Crawford, Gregory Collins, Francis Shinn, Paul Leipzig, Jeremy Hannenhalli, Sridhar Berry, Charles C Ecker, Joseph R Bushman, Frederic D PLoS Pathog Research Article Retroviruses differ in their preferences for sites for viral DNA integration in the chromosomes of infected cells. Human immunodeficiency virus (HIV) integrates preferentially within active transcription units, whereas murine leukemia virus (MLV) integrates preferentially near transcription start sites and CpG islands. We investigated the viral determinants of integration-site selection using HIV chimeras with MLV genes substituted for their HIV counterparts. We found that transferring the MLV integrase (IN) coding region into HIV (to make HIVmIN) caused the hybrid to integrate with a specificity close to that of MLV. Addition of MLV gag (to make HIVmGagmIN) further increased the similarity of target-site selection to that of MLV. A chimeric virus with MLV Gag only (HIVmGag) displayed targeting preferences different from that of both HIV and MLV, further implicating Gag proteins in targeting as well as IN. We also report a genome-wide analysis indicating that MLV, but not HIV, favors integration near DNase I–hypersensitive sites (i.e., +/− 1 kb), and that HIVmIN and HIVmGagmIN also favored integration near these features. These findings reveal that IN is the principal viral determinant of integration specificity; they also reveal a new role for Gag-derived proteins, and strengthen models for integration targeting based on tethering of viral IN proteins to host proteins. Public Library of Science 2006-06 2006-06-23 /pmc/articles/PMC1480600/ /pubmed/16789841 http://dx.doi.org/10.1371/journal.ppat.0020060 Text en © 2006 Lewinski et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Lewinski, Mary K
Yamashita, Masahiro
Emerman, Michael
Ciuffi, Angela
Marshall, Heather
Crawford, Gregory
Collins, Francis
Shinn, Paul
Leipzig, Jeremy
Hannenhalli, Sridhar
Berry, Charles C
Ecker, Joseph R
Bushman, Frederic D
Retroviral DNA Integration: Viral and Cellular Determinants of Target-Site Selection
title Retroviral DNA Integration: Viral and Cellular Determinants of Target-Site Selection
title_full Retroviral DNA Integration: Viral and Cellular Determinants of Target-Site Selection
title_fullStr Retroviral DNA Integration: Viral and Cellular Determinants of Target-Site Selection
title_full_unstemmed Retroviral DNA Integration: Viral and Cellular Determinants of Target-Site Selection
title_short Retroviral DNA Integration: Viral and Cellular Determinants of Target-Site Selection
title_sort retroviral dna integration: viral and cellular determinants of target-site selection
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1480600/
https://www.ncbi.nlm.nih.gov/pubmed/16789841
http://dx.doi.org/10.1371/journal.ppat.0020060
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