Identification of SNF2h, a Chromatin-Remodeling Factor, as a Novel Binding Protein of Vpr of Human Immunodeficiency Virus Type 1

Taneichi, Daiki; Iijima, Kenta; Doi, Atsushi; Koyama, Tsutomu; Minemoto, Yuzuru; Tokunaga, Kenzo; Shimura, Mari; Kano, Shigeyuki; Ishizaka, Yukihito

doi:10.1007/s11481-011-9276-5

Cited by 5 publications

(3 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To test this hypothesis, we checked whether infection with R+ virus induced the DNA damage response in MDMs (Figure 7A). In agreement with our previous observations, infection with R+ virus evoked the cellular response triggered by DNA damage [36,37,41,42]. We investigated the infectivity of R+ virus and observed that Vpr enhanced viral transduction in the presence of RAL, which was blocked by AZT (Figure 7B).…”

Section: Resultssupporting

confidence: 91%

DNA damage enhances integration of HIV-1 into macrophages by overcoming integrase inhibition

et al. 2013

Self Cite

View full text Add to dashboard Cite

BackgroundThe prevention of persistent human immunodeficiency virus type 1 (HIV-1) infection requires the clarification of the mode of viral transduction into resting macrophages. Recently, DNA double-strand breaks (DSBs) were shown to enhance infection by D64A virus, which has a defective integrase catalytic activity (IN-CA). However, the mechanism by which DSBs upregulate viral transduction was unclear. Here we analyzed the roles of DSBs during IN-CA–independent viral transduction into macrophages.ResultsWe used cellular systems with rare-cutting endonucleases and found that D64A virus integrated efficiently into the sites of artificially induced DSBs. This IN-CA-independent viral transduction was blocked by an inhibitor of ataxia telangiectasia mutated protein (ATM) but was resistant to raltegravir (RAL), an inhibitor of integrase activity during strand transfer. Moreover, Vpr, an accessory gene product of HIV-1, induced DSBs in resting macrophages and significantly enhanced the rate of IN-CA-independent viral transduction into macrophages with concomitant production of secondary viruses.ConclusionDSBs contribute to the IN-CA–independent viral infection of macrophages, which is resistant to RAL. Thus, the ATM-dependent cellular pathway and Vpr-induced DNA damage are novel targets for preventing persistent HIV-1 infection.

show abstract

Section: Resultssupporting

confidence: 91%

DNA damage enhances integration of HIV-1 into macrophages by overcoming integrase inhibition

et al. 2013

Self Cite

View full text Add to dashboard Cite

show abstract

“…Previous reports have shown that Vpr associates with chromatin, though the percentage of Vpr bound to the chromatin fraction was not determined [22,23,40,41]. Importantly, biochemical and immunofluorescence approaches showed that Vpr could form a complex with DCAF1 on chromatin [22].…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Vpr Induces the Degradation of ZIP and sZIP, Adaptors of the NuRD Chromatin Remodeling Complex, by Hijacking DCAF1/VprBP

et al. 2013

View full text Add to dashboard Cite

The Vpr protein from type 1 and type 2 Human Immunodeficiency Viruses (HIV-1 and HIV-2) is thought to inactivate several host proteins through the hijacking of the DCAF1 adaptor of the Cul4A ubiquitin ligase. Here, we identified two transcriptional regulators, ZIP and sZIP, as Vpr-binding proteins degraded in the presence of Vpr. ZIP and sZIP have been shown to act through the recruitment of the NuRD chromatin remodeling complex. Strikingly, chromatin is the only cellular fraction where Vpr is present together with Cul4A ubiquitin ligase subunits. Components of the NuRD complex and exogenous ZIP and sZIP were also associated with this fraction. Several lines of evidence indicate that Vpr induces ZIP and sZIP degradation by hijacking DCAF1: (i) Vpr induced a drastic decrease of exogenously expressed ZIP and sZIP in a dose-dependent manner, (ii) this decrease relied on the proteasome activity, (iii) ZIP or sZIP degradation was impaired in the presence of a DCAF1-binding deficient Vpr mutant or when DCAF1 expression was silenced. Vpr-mediated ZIP and sZIP degradation did not correlate with the growth-related Vpr activities, namely G2 arrest and G2 arrest-independent cytotoxicity. Nonetheless, infection with HIV-1 viruses expressing Vpr led to the degradation of the two proteins. Altogether our results highlight the existence of two host transcription factors inactivated by Vpr. The role of Vpr-mediated ZIP and sZIP degradation in the HIV-1 replication cycle remains to be deciphered.

show abstract

“…Considering that Cul4 regulates H2B ubiquitination for facilitating the DDR [ 53 ] and that the Q65R mutant is ubiquitination-defective due to its inability to bind DDB1/VprBP [ 21 , 22 ], it is plausible that H2B is a target of Vpr-mediated ubiquitination, which is critical for Vpr-induced RPA70 loading. In addition to histone H2B, the association of Vpr with several chromatin modification factors, including p300, SNF2 h, NuRD and HDAC1 [ 38 , 54 – 56 ], may also contribute to the efficient reorganization of chromatin. Our data suggested that the concerted actions of structural alteration of DNA and chromatin remodelling are required for efficient RPA70 loading by Vpr.…”

Section: Discussionmentioning

confidence: 99%

Structural alteration of DNA induced by viral protein R of HIV-1 triggers the DNA damage response

2018

Self Cite

View full text Add to dashboard Cite

BackgroundViral protein R (Vpr) is an accessory protein of HIV-1, which is potentially involved in the infection of macrophages and the induction of the ataxia-telangiectasia and Rad3-related protein (ATR)-mediated DNA damage response (DDR). It was recently proposed that the SLX4 complex of structure-specific endonuclease is involved in Vpr-induced DDR, which implies that aberrant DNA structures are responsible for this phenomenon. However, the mechanism by which Vpr alters the DNA structures remains unclear.ResultsWe found that Vpr unwinds double-stranded DNA (dsDNA) and invokes the loading of RPA70, which is a single-stranded DNA-binding subunit of RPA that activates the ATR-dependent DDR. We demonstrated that Vpr influenced RPA70 to accumulate in the corresponding region utilizing the LacO/LacR system, in which Vpr can be tethered to the LacO locus. Interestingly, RPA70 recruitment required chromatin remodelling via Vpr-mediated ubiquitination of histone H2B. On the contrary, Q65R mutant of Vpr, which lacks ubiquitination activity, was deficient in both chromatin remodelling and RPA70 loading on to the chromatin. Moreover, Vpr-induced unwinding of dsDNA coincidently resulted in the accumulation of negatively supercoiled DNA and covalent complexes of topoisomerase 1 and DNA, which caused DNA double-strand breaks (DSBs) and DSB-directed integration of proviral DNA. Lastly, we noted the dependence of Vpr-promoted HIV-1 infection in resting macrophages on topoisomerase 1.ConclusionsThe findings of this study indicate that Vpr-induced structural alteration of DNA is a primary event that triggers both DDR and DSB, which ultimately contributes to HIV-1 infection.Electronic supplementary materialThe online version of this article (10.1186/s12977-018-0391-8) contains supplementary material, which is available to authorized users.

show abstract

Identification of SNF2h, a Chromatin-Remodeling Factor, as a Novel Binding Protein of Vpr of Human Immunodeficiency Virus Type 1

Cited by 5 publications

References 49 publications

DNA damage enhances integration of HIV-1 into macrophages by overcoming integrase inhibition

DNA damage enhances integration of HIV-1 into macrophages by overcoming integrase inhibition

HIV-1 Vpr Induces the Degradation of ZIP and sZIP, Adaptors of the NuRD Chromatin Remodeling Complex, by Hijacking DCAF1/VprBP

Structural alteration of DNA induced by viral protein R of HIV-1 triggers the DNA damage response

Contact Info

Product

Resources

About