Retroviral prototype foamy virus intasome binding to a nucleosome target does not determine integration efficiency

Retroviral integrases must navigate host DNA packaged as chromatin during integration of the viral genome. Prototype foamy virus (PFV) integrase (IN) forms a tetramer bound to two viral DNA (vDNA) ends in a complex termed an intasome. PFV IN consists of four domains: the amino terminal extension domain (NED), amino terminal domain (NTD), catalytic core domain (CCD), and carboxyl terminal domain (CTD). The domains of the two inner IN protomers have been visualized, as well as the CCDs of the two outer IN protomers. However, the roles of the amino and carboxyl terminal domains of the PFV intasome outer subunits during integration to a nucleosome target substrate are not clear. We used the well-characterized 601 nucleosome to assay integration activity as well as intasome binding. PFV intasome integration to 601 nucleosomes occurs in clusters at four independent sites. We find that the outer protomer NED and NTD domains have no significant effects on integration efficiency, site selection, or binding. The CTDs of the outer PFV intasome subunits dramatically affect nucleosome binding but have little effect on total integration efficiency. The outer PFV IN CTDs did significantly alter the integration efficiency at one site. Histone tails also significantly affect intasome binding, but have little impact on PFV integration efficiency or site selection. These results indicate that binding to nucleosomes does not correlate with integration efficiency and suggests most intasome-binding events are unproductive. Retroviral integrases must navigate host DNA packaged as chromatin during integration of the viral genome. Prototype foamy virus (PFV) integrase (IN) forms a tetramer bound to two viral DNA (vDNA) ends in a complex termed an intasome. PFV IN consists of four domains: the amino terminal extension domain (NED), amino terminal domain (NTD), catalytic core domain (CCD), and carboxyl terminal domain (CTD). The domains of the two inner IN protomers have been visualized, as well as the CCDs of the two outer IN protomers. However, the roles of the amino and carboxyl terminal domains of the PFV intasome outer subunits during integration to a nucleosome target substrate are not clear. We used the well-characterized 601 nucleosome to assay integration activity as well as intasome binding. PFV intasome integration to 601 nucleosomes occurs in clusters at four independent sites. We find that the outer protomer NED and NTD domains have no significant effects on integration efficiency, site selection, or binding. The CTDs of the outer PFV intasome subunits dramatically affect nucleosome binding but have little effect on total integration efficiency. The outer PFV IN CTDs did significantly alter the integration efficiency at one site. Histone tails also significantly affect intasome binding, but have little impact on PFV integration efficiency or site selection. These results indicate that binding to nucleosomes does not correlate with integration efficiency and suggests most intasome-binding events are unproductive. Following entry to a cell, the retroviral enzyme reverse transcriptase copies the viral genomic RNA to a linear double-stranded cDNA (1Coffin J.M. Hughes S.H. Varmus H.E. Retroviruses. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY1997Google Scholar). Then retroviral integrase (IN) covalently joins the cDNA 3′ ends to host DNA. The integration reaction is faithfully recapitulated in vitro by complexes assembled from recombinant IN and oligomers mimicking the viral DNA ends (vDNA), termed intasomes (2Maertens G.N. Hare S. Cherepanov P. The mechanism of retroviral integration from X-ray structures of its key intermediates.Nature. 2010; 468: 326-329Crossref PubMed Scopus (250) Google Scholar). The IN of prototype foamy virus (PFV) has four domains: an amino terminal extension domain (NED), an amino terminal domain (NTD), a catalytic core domain (CCD), and a carboxyl terminal domain (CTD) (3Valkov E. Gupta S.S. Hare S. Helander A. Roversi P. McClure M. Cherepanov P. Functional and structural characterization of the integrase from the prototype foamy virus.Nucleic Acids Res. 2009; 37: 243-255Crossref PubMed Scopus (120) Google Scholar). Structural studies of PFV intasomes revealed a tetramer of IN arranged with two catalytically active inner protomers and two structurally important outer protomers (2Maertens G.N. Hare S. Cherepanov P. The mechanism of retroviral integration from X-ray structures of its key intermediates.Nature. 2010; 468: 326-329Crossref PubMed Scopus (250) Google Scholar, 4Hare S. Gupta S.S. Valkov E. Engelman A. Cherepanov P. Retroviral intasome assembly and inhibition of DNA strand transfer.Nature. 2010; 464: 232-236Crossref PubMed Scopus (555) Google Scholar, 5Maskell D.P. Renault L. Serrao E. Lesbats P. Matadeen R. Hare S. Lindemann Engelman A. Cherepanov P. Structural retroviral integration PubMed Scopus Google Scholar). IN domains of the PFV intasome inner protomers have been visualized, but the CCDs of the outer protomers have been to the IN tetramer retroviral intasomes also an of in the of virus and or a of as with virus A. M. Cherepanov P. Engelman a integrase intasome PubMed Scopus Google Scholar, A. D.P. Serrao E. P. A. Engelman A. Cherepanov P. assembly DNA PubMed Scopus Google Scholar, S. S. D.P. of the virus PubMed Scopus Google Scholar). to the is a intasome core structurally to the PFV IN tetramer Cherepanov P. Retroviral intasomes PubMed Scopus Google Scholar). The suggests that the PFV intasome as a intasomes of The target retroviral integration is consists of DNA packaged of nucleosome is of DNA an of and DNA and a of the nucleosome core at PubMed Scopus Google Scholar). assembled from recombinant and a nucleosome DNA S. of nucleosome core from recombinant and PubMed Scopus Google Scholar). on the of and nucleosome of genomic S. A. PubMed Scopus Google Scholar). termed 601 in vitro to a of has been to nucleosome in DNA binding to and nucleosome PubMed Scopus Google Scholar, J.M. A. A. in is of a nucleosome in 2010; PubMed Scopus Google Scholar). The DNA is to with the at the and the ends termed 601 DNA to a at the the A. of to DNA target occurs a mechanism that is from nucleosome PubMed Scopus Google Scholar, S. R. R. of the nucleosome DNA Acids Res. PubMed Scopus Google Scholar). retroviral integration has been to in the of chromatin virus integrase integration to of DNA the nucleosome S. A. PubMed Scopus Google Scholar, R. The of DNA and nucleosome on integration events by PubMed Google Scholar, Varmus H.E. and DNA retroviral integration target site PubMed Scopus Google Scholar). intasome with nucleosomes on of chromatin R. DNA does not affect prototype foamy virus integration efficiency or site PubMed Scopus Google Scholar). or DNA on of nucleosomes to a binding site A. of to DNA target occurs a mechanism that is from nucleosome PubMed Scopus Google Scholar, S. R. R. of the nucleosome DNA Acids Res. PubMed Scopus Google Scholar, M. Histone core DNA PubMed Scopus Google Scholar, A. of DNA in on a PubMed Scopus Google Scholar, S. M. A. R. by 2009; PubMed Scopus Google Scholar). PFV intasomes are also of on DNA and in with linear DNA R. Retroviral intasomes a target DNA by results in PubMed Scopus Google Scholar). PFV intasomes on DNA to an integration site by a mechanism to However, nucleosomes with that no effect on integration efficiency R. DNA does not affect prototype foamy virus integration efficiency or site PubMed Scopus Google Scholar). suggests that intasomes not to DNA by on is from an of the PFV intasome bound to a nucleosome the of an inner IN protomer bound to an D.P. Renault L. Serrao E. Lesbats P. Matadeen R. Hare S. Lindemann Engelman A. Cherepanov P. Structural retroviral integration PubMed Scopus Google Scholar). as virus or virus host to integration complexes to nucleosomes by binding IN and A. A. E. S.S. L. M. virus integration at S. A. PubMed Scopus Google Scholar, S. S. R. The of virus integration PubMed Scopus Google Scholar, and and to the of PubMed Scopus Google Scholar, Hughes S. P. Cherepanov P. Engelman A. from complex to effect PubMed Scopus Google Scholar). PFV intasomes to to nucleosomes to integration DNA. Structural studies a to PFV IN protomers at the inner or outer intasome subunits by D.P. Renault L. Serrao E. Lesbats P. Matadeen R. Hare S. Lindemann Engelman A. Cherepanov P. Structural retroviral integration PubMed Scopus Google Scholar). PFV and PFV IN to the catalytically active inner or outer of the or domains at the outer protomers by the D.P. Renault L. Serrao E. Lesbats P. Matadeen R. Hare S. Lindemann Engelman A. Cherepanov P. Structural retroviral integration PubMed Scopus Google Scholar). The assembled with and to active PFV intasomes D.P. Renault L. Serrao E. Lesbats P. Matadeen R. Hare S. Lindemann Engelman A. Cherepanov P. Structural retroviral integration PubMed Scopus Google Scholar, Prototype foamy virus intasome is by outer domains and by PubMed Scopus Google Scholar). revealed that the outer protomer and domains are not Prototype foamy virus intasome is by outer domains and by PubMed Scopus Google Scholar, M. S. R. domains of integrase retroviral intasomes are of DNA PubMed Scopus Google Scholar). of the outer protomer CTDs to of the PFV intasomes binding to a target DNA Prototype foamy virus intasome is by outer domains and by PubMed Scopus Google Scholar). of the amino terminal domains of the outer protomers effects on intasome the outer protomer and domains roles in PFV integration to chromatin is The effects of outer protomer during integration to nucleosomes have not been at in the assembled as well as PFV intasomes with of the IN amino terminal NED and NTD domains or of the IN at the outer protomers. efficiency and integration to the 601 nucleosome structures of nucleosome core the 2010; PubMed Scopus Google PFV intasomes to 601 nucleosomes in four clusters at of the outer PFV IN domains effects on integration efficiency or site selection. These effects at a integration and in the of binding of the to PFV intasome and by PFV intasomes significantly binding to with to the roles of tails on integration efficiency and binding at of tails significant effects on intasome binding, no significant in integration efficiency. The of integration did not correlate with significant in binding, that PFV intasome binding to a target is not PFV intasomes are a tetramer of IN and two (2Maertens G.N. Hare S. Cherepanov P. The mechanism of retroviral integration from X-ray structures of its key intermediates.Nature. 2010; 468: 326-329Crossref PubMed Scopus (250) Google Scholar). These complexes integration to target DNA in vitro (3Valkov E. Gupta S.S. Hare S. Helander A. Roversi P. McClure M. Cherepanov P. Functional and structural characterization of the integrase from the prototype foamy virus.Nucleic Acids Res. 2009; 37: 243-255Crossref PubMed Scopus (120) Google Scholar). integration is the of to target DNA in a reaction termed strand The two of are by of target DNA integration to a linear target DNA two of one and a of the target DNA. DNA is at the of and target DNA. of linear DNA a The 601 DNA is to with the from nucleosome are two linear DNA of to target DNA. of the or strand of the 601 of the of on strand and intasomes one to the target a DNA These integration are not to but during integration in with PFV intasomes have been at (2Maertens G.N. Hare S. Cherepanov P. The mechanism of retroviral integration from X-ray structures of its key intermediates.Nature. 2010; 468: 326-329Crossref PubMed Scopus (250) Google Scholar, M. S. R. domains of integrase retroviral intasomes are of DNA PubMed Scopus Google Scholar). of PFV intasome integration with a target DNA that the reaction by at in the of a Prototype foamy virus intasome is by outer domains and by PubMed Scopus Google Scholar). the of integration with nucleosome PFV intasomes with from recombinant and 601 DNA one with a to of or are not integration at R. DNA does not affect prototype foamy virus integration efficiency or site PubMed Scopus Google Scholar). revealed integration that and 601 DNA. and at The of PFV intasome integration to a nucleosome target are with integration to substrate Prototype foamy virus intasome is by outer domains and by PubMed Scopus Google Scholar). These reaction integration with 601 However, the at the integration site the of DNA and of integration DNA is S. A. PubMed Scopus Google Scholar, that of one or dramatically the of PubMed Scopus Google Scholar). of integration by that the are one is to the target results in a DNA. The of a with a is D.P. Renault L. Serrao E. Lesbats P. Matadeen R. Hare S. Lindemann Engelman A. Cherepanov P. Structural retroviral integration PubMed Scopus Google Scholar). integration with PFV intasome integration to nucleosomes These of the in that PFV intasomes integration to nucleosome PFV intasome integration nucleosomes by to the strand in nucleosome DNA. strand a in the target DNA The 601 DNA the of the or strand and The that is 3′ to the strand the is to integration site and of the strand and of its The of the indicate of integration that to the 601 nucleosome structures of nucleosome core the 2010; PubMed Scopus Google Scholar). of PFV intasomes to nucleosomes with 601 DNA on the or strand revealed that PFV integration in as R. DNA does not affect prototype foamy virus integration efficiency or site PubMed Scopus Google Scholar). clusters of integration of the at the of from with the intasome to These as a of The four clusters of integration with nucleosomes are at 601 and the four integration are at and The integration with and by the of strand a a of correlate with a of the clusters are to by the integration with retroviral integration with PFV integration is at the virus integrase integration to of DNA the nucleosome S. A. PubMed Scopus Google Scholar, R. The of DNA and nucleosome on integration events by PubMed Google Scholar). The and from to linear and to the strand events on the two The of integration the and in and the of in that PFV intasome integration to nucleosomes is efficiency from the the of in the Following to the of the The the by the total to the integration efficiency as of The revealed clusters of two to two at at four at and two at revealed a of PFV integration the the and the the most of site the and the integration clusters to a 601 nucleosome revealed that are on DNA and are not by the or DNA structures of nucleosome core the 2010; PubMed Scopus Google Scholar). domains of the inner PFV IN protomers have been structurally and the viral DNA (2Maertens G.N. Hare S. Cherepanov P. The mechanism of retroviral integration from X-ray structures of its key intermediates.Nature. 2010; 468: 326-329Crossref PubMed Scopus (250) Google Scholar). bound to a the of one inner PFV IN protomer also the amino terminal of D.P. Renault L. Serrao E. Lesbats P. Matadeen R. Hare S. Lindemann Engelman A. Cherepanov P. Structural retroviral integration PubMed Scopus Google Scholar). the CCDs of the outer PFV IN protomers The outer PFV IN CCDs structurally important tetramer but not viral or target S. Gupta S.S. Valkov E. Engelman A. Cherepanov P. Retroviral intasome assembly and inhibition of DNA strand transfer.Nature. 2010; 464: 232-236Crossref PubMed Scopus (555) Google Scholar, 5Maskell D.P. Renault L. Serrao E. Lesbats P. Matadeen R. Hare S. Lindemann Engelman A. Cherepanov P. Structural retroviral integration PubMed Scopus Google Scholar). PFV to the inner protomers and PFV to the outer protomers D.P. Renault L. Serrao E. Lesbats P. Matadeen R. Hare S. Lindemann Engelman A. Cherepanov P. Structural retroviral integration PubMed Scopus Google Scholar). of at the outer protomers with catalytically active inner protomers. 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DNA does not affect prototype foamy virus integration efficiency or site PubMed Scopus Google Scholar). studies have that retroviral integration occurs at DNA of a nucleosome or DNA virus integrase integration to of DNA the nucleosome S. A. PubMed Scopus Google Scholar, R. The of DNA and nucleosome on integration events by PubMed Google Scholar, Varmus H.E. DNA retroviral in PubMed Scopus Google Scholar). Structural of the 601 nucleosome an at structures of nucleosome core the 2010; PubMed Scopus Google Scholar, The DNA of the Acids Res. PubMed Scopus Google Scholar). The DNA on the 601 nucleosome from the DNA of the nucleosome at that the DNA is S. of chromatin bound to the nucleosome core 2010; PubMed Scopus Google Scholar, S. and PubMed Scopus Google Scholar). The 601 is significantly at and DNA an with DNA and the that retroviral integrases the most of DNA. 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