Single cell analysis of Daxx and ATRX-dependent transcriptional repression

Newhart, Alyshia; Rafalska-Metcalf, Ilona U.; Yang, Tian; Negorev, Dmitri; Janicki, Susan M.

doi:10.1242/jcs.110148

Cited by 43 publications

(61 citation statements)

References 57 publications

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“…PML/ND10-dependent gene silencing is through the formation of heterochromatin structures on promoters (Newhart et al, 2012). This results in reduced virus yield if not counteracted by virusencoded proteins, ICP0/RL2 for HSV-1 and ORF61 for VZV (Everett et al, 2006(Everett et al, , 2010, or inactivation of histone deacetylase by phosphorylation by virus serine/threonine kinase, US3 for HSV-1 and ORF66p for VZV (Walters et al, 2010).…”

Section: Fate Of Incoming Dnamentioning

confidence: 99%

“…Once targeted to virus DNA through Sp100 binding to hypomethylated CpG islands, HDaxx, an essential multifunctional PML/ND10 component, suppresses transcription by recruiting histone-modifying enzymes, histone deacetylase 1 and 2 (Lukashchuk & Everett, 2010). PML/ND10-dependent gene silencing is through the formation of heterochromatin structures on promoters (Newhart et al, 2012). This results in reduced virus yield if not counteracted by virusencoded proteins, ICP0/RL2 for HSV-1 and ORF61 for VZV (Everett et al, 2006(Everett et al, , 2010, or inactivation of histone deacetylase by phosphorylation by virus serine/threonine kinase, US3 for HSV-1 and ORF66p for VZV (Walters et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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A comparison of herpes simplex virus type 1 and varicella-zoster virus latency and reactivation

Kennedy

Rovnak

Badani

et al. 2015

Journal of General Virology

137

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Herpes simplex virus type 1 (HSV-1; human herpesvirus 1) and varicella-zoster virus (VZV; human herpesvirus 3) are human neurotropic alphaherpesviruses that cause lifelong infections in ganglia. Following primary infection and establishment of latency, HSV-1 reactivation typically results in herpes labialis (cold sores), but can occur frequently elsewhere on the body at the site of primary infection (e.g. whitlow), particularly at the genitals. Rarely, HSV-1 reactivation can cause encephalitis; however, a third of the cases of HSV-1 encephalitis are associated with HSV-1 primary infection. Primary VZV infection causes varicella (chickenpox) following which latent virus may reactivate decades later to produce herpes zoster (shingles), as well as an increasingly recognized number of subacute, acute and chronic neurological conditions. Following primary infection, both viruses establish a latent infection in neuronal cells in human peripheral ganglia. However, the detailed mechanisms of viral latency and reactivation have yet to be unravelled. In both cases latent viral DNA exists in an 'end-less' state where the ends of the virus genome are joined to form structures consistent with unit length episomes and concatemers, from which viral gene transcription is restricted. In latently infected ganglia, the most abundantly detected HSV-1 RNAs are the spliced products originating from the primary latency associated transcript (LAT). This primary LAT is an 8.3 kb unstable transcript from which two stable (1.5 and 2.0 kb) introns are spliced. Transcripts mapping to 12 VZV genes have been detected in human ganglia removed at autopsy; however, it is difficult to ascribe these as transcripts present during latent infection as early-stage virus reactivation may have transpired in the post-mortem time period in the ganglia. Nonetheless, low-level transcription of VZV ORF63 has been repeatedly detected in multiple ganglia removed as close to death as possible. There is increasing evidence that HSV-1 and VZV latency is epigenetically regulated. In vitro models that permit pathway analysis and identification of both epigenetic modulations and global transcriptional mechanisms of HSV-1 and VZV latency hold much promise for our future understanding in this complex area. This review summarizes the molecular biology of HSV-1 and VZV latency and reactivation, and also presents future directions for study. Received 5 January 2015Accepted 18 March 2015 IntroductionHerpes simplex virus type 1 (HSV-1; human herpesvirus 1) and varicella-zoster virus (VZV; human herpesvirus 3) are human neurotropic alphaherpesviruses usually acquired early in life. Primary HSV-1 infection is usually localized and may be asymptomatic, although it can produce a more widespread systemic infection in neonates and immunocompromised adults, whilst primary VZV infection is systemic and results in childhood varicella (chickenpox). During primary infection, both viruses gain access to neurons most likely through retrograde transport from the site of cutaneous lesion...

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Section: Fate Of Incoming Dnamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A comparison of herpes simplex virus type 1 and varicella-zoster virus latency and reactivation

Kennedy

Rovnak

Badani

et al. 2015

Journal of General Virology

137

View full text Add to dashboard Cite

show abstract

“…For example, incoming DNA, from viral infection or DNA transfection, is located in the vicinity of ND10s and leads to enlarged ND10s (19)(20)(21). ND10 components-Daxx and ATRX-are found to regulate histone assembly on minigenes introduced into the cell (22). Moreover, many chromatin-remodeling proteins such as CoREST and CLOCK are recruited to ND10s upon infection (23,24).…”

mentioning

confidence: 99%

Interaction of Herpes Simplex Virus ICP0 with ND10 Bodies: a Sequential Process of Adhesion, Fusion, and Retention

Zheng

Roizman

2013

J Virol

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On entry into the nucleus, herpes simplex virus 1 (HSV-1) DNA localizes to nuclear bodies known as ND10. Gene repression imposed by ND10 is released by a viral protein, ICP0, via degradation of the ND10 constituents promyelocytic leukemia protein (PML) and Sp100 and the subsequent dispersal of ND10 bodies. In order to understand the dynamic interaction between ICP0 and ND10, we carried out deletion mapping to identify the domains of ICP0 responsible for its association with ND10. Here, we report the following. (i) An ND10 entry signal (ND10-ES), located between residues 245 and 474, is required for ICP0 to penetrate and fuse with ND10. ICP0 lacking ND10-ES adheres to the surface of ND10 but fails to enter. (ii) In the absence of ND10-ES, the E3 ubiquitin ligase of ICP0 facilitates the transient adhesion of the truncated ICP0 to the ND10 surface, whereas the presence of ND10-ES in ICP0 renders ND10 fusion regardless of the E3 ligase activity. (iii) The C terminus of ICP0 is required for retention of ICP0 in ND10 but plays no role in the recruitment process. (iv) The adverse effects of an inactive RING domain on viral replication are partially reversed by deleting either ND10-ES or the C-terminal retention domain, suggesting that additional ICP0 functions require the release of ICP0 from ND10. Based on these results, we conclude that association of ICP0 and ND10 is a dynamic process, in which three sequential steps-adhesion, fusion, and retention-are adopted to stabilize the interaction. A faithful execution of these steps defines the ultimate productivity of the virus.

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“…Moreover, recent structural data from Elsässer and colleagues show that DAXX envelops the (H3.3-H4) dimer in a manner excluding interaction with ASF1 or DNA (Elsasser et al 2012). DAXX and ATRX deposit (H3.3-H4) into telomeric and pericentric chromatin (Drane et al 2010;Goldberg et al 2010;Lewis et al 2010;Wong et al 2010), and both are required for chromatin assembly and transcriptional repression of transgene arrays (Newhart et al 2012). In mouse embryonic cortical neurons, DAXX is involved in H3.3 deposition into regulatory elements of several genes activated upon neuronal induction (Michod et al 2012).…”

mentioning

confidence: 99%

DAXX-dependent supply of soluble (H3.3–H4) dimers to PML bodies pending deposition into chromatin

et al. 2012

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Replication-independent chromatin deposition of histone variant H3.3 is mediated by several chaperones. We report a multistep targeting of newly synthesized epitope-tagged H3.3 to chromatin via PML bodies. H3.3 is recruited to PML bodies in a DAXX-dependent manner, a process facilitated by ASF1A. DAXX is required for enrichment of ATRX, but not ASF1A or HIRA, with PML. Nonetheless, the chaperones colocalize with H3.3 at PML bodies and are found in one or more complexes with PML. Both DAXX and PML are necessary to prevent accumulation of a soluble, nonincorporated pool of H3.3. H3.3 targeting to PML is enhanced with an (H3.3-H4) 2 tetramerization mutant of H3.3, suggesting H3.3 recruitment to PML as an (H3.3-H4) dimer rather than as a tetramer. Our data support a model of DAXX-mediated recruitment of (H3.3-H4) dimers to PML bodies, which may function as triage centers for H3.3 deposition into chromatin by distinct chaperones.

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Single cell analysis of Daxx and ATRX-dependent transcriptional repression

Cited by 43 publications

References 57 publications

A comparison of herpes simplex virus type 1 and varicella-zoster virus latency and reactivation

A comparison of herpes simplex virus type 1 and varicella-zoster virus latency and reactivation

Interaction of Herpes Simplex Virus ICP0 with ND10 Bodies: a Sequential Process of Adhesion, Fusion, and Retention

DAXX-dependent supply of soluble (H3.3–H4) dimers to PML bodies pending deposition into chromatin

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