HCMV-Infected Cells Maintain Efficient Nucleotide Excision Repair of the Viral Genome while Abrogating Repair of the Host Genome

O’Dowd, John M.; Zavala, Anamaria G.; Brown, Celeste J.; Mori, Toshio; Fortunato, Elizabeth A.

doi:10.1371/journal.ppat.1003038

Cited by 25 publications

(31 citation statements)

References 76 publications

(96 reference statements)

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“…To provide areas in the nucleus for replication compartments to develop, the compaction and movement of chromatin is observed (O'Dowd et al, 2012; Strang et al, 2012b Several facets of HCMV replication compartment organization and function late in infection have recently been described, each involving the localization of HCMV protein UL44. UL44 is the putative processivity subunit of the HCMV DNA polymerase (Ertl & Powell, 1992), and several different phosphorylated forms of UL44 are present in the infected cell (Silva et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…However, the full repertoire of viral and cellular proteins acting in concert during DNA synthesis has yet to be described. These proteins probably include those viral and cellular proteins that associate with UL44 and/or UL84 (Gao et al, 2008;Strang et al, 2009Strang et al, , 2010a, several proteins that have illdefined roles in viral DNA synthesis (for example, UL36, IRS1 and IE2; Sarisky & Hayward, 1996), plus viral and cellular proteins involved in DNA damage responses and viral DNA repair O'Dowd et al, 2012;. How these and other proteins are organized within HCMV replication compartments is unclear but may involve UL44.…”

Section: Introductionmentioning

confidence: 99%

“…To provide areas in the nucleus for replication compartments to develop, the compaction and movement of chromatin is observed (O'Dowd et al, 2012;Strang et al, 2012b). This process is termed 'chromatin partitioning'.…”

Section: Introductionmentioning

confidence: 99%

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Viral and cellular subnuclear structures in human cytomegalovirus-infected cells

Strang

2015

Journal of General Virology

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In human cytomegalovirus (HCMV)-infected cells, a dramatic remodelling of the nuclear architecture is linked to the creation, utilization and manipulation of subnuclear structures. This review outlines the involvement of several viral and cellular subnuclear structures in areas of HCMV replication and virus-host interaction that include viral transcription, viral DNA synthesis and the production of DNA-filled viral capsids. The structures discussed include those that promote or impede HCMV replication (such as viral replication compartments and promyelocytic leukaemia nuclear bodies, respectively) and those whose role in the infected cell is unclear (for example, nucleoli and nuclear speckles). Viral and cellular proteins associated with subnuclear structures are also discussed. The data reviewed here highlight advances in our understanding of HCMV biology and emphasize the complexity of HCMV replication and virus-host interactions in the nucleus. IntroductionThe betaherpesvirus human cytomegalovirus (HCMV) is a widespread opportunistic pathogen that severely affects immunocompromised and immunodeficient populations (Mocarski et al., 2007). Like all herpesviruses, HCMV undergoes either productive or latent infection. During productive infection, infectious virus is produced, while in latent infection the virus becomes largely transcriptionally quiescent (Mocarski et al., 2007). Like other herpesviruses, many events that are critical for productive HCMV replication take place within the nucleus. These include essential steps in viral replication, such as: the transcriptional cascade of immediate-early (IE), early and late viral RNA transcripts, synthesis of viral DNA and the production of DNA-containing capsids (Mocarski et al., 2007). Compared with the prototype human herpesvirus, the alphaherpesvirus herpes simplex virus (HSV), certain features of productive HCMV infection are not well characterized. However, it is clear that several subnuclear structures are involved in HCMV genome replication and virus-host interactions. Uncovering the roles of these structures has led to significant advances in our understanding of HCMV biology. This review summarizes the involvement of several viral and cellular subnuclear structures in productive HCMV infection. The participation of each structure in HCMV replication and virus-host interactions is described from entry of the viral genome into the nucleus to the egress of viral capsids through the nuclear membrane. The data discussed highlight recent advances in our understanding of subnuclear structure function, introduce viral and cellular factors associated with subnuclear structures and indicate what questions have yet to be answered.Entry of the HCMV genome into the nucleus: the nuclear pore complex, nuclear speckles, promyelocytic leukaemia protein nuclear bodies and pp150 bodies HCMV genome entry into the nucleus is poorly defined but may be similar to movement of the HSV DNA genome through the nuclear pore complex (NPC) (Kobiler et al., 2012) (Fig. 1a). HCMV capsid ...

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Viral and cellular subnuclear structures in human cytomegalovirus-infected cells

Strang

2015

Journal of General Virology

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“…In fibroblasts, large bipolar viral replication centers (RCs) are formed within 48 h postinfection (hpi) and certain host cellular proteins become strongly associated with these RCs (1; reviewed in reference 2). These proteins include the regulatory protein p53 (3), as well as numerous components of the host cellular DNA damage response (DDR) and repair pathways (4)(5)(6)(7)(8).…”

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confidence: 99%

“…Some viruses appear to require DDR proteins for efficient replication (10,11), while for other viruses an efficient DDR can be detrimental to their DNA replication (12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Studies from several labs, including our own, have shown that HCMV infection initiates the ataxia telangiectasia mutated (ATM)-dependent double-strand break (DSB) DDR (4)(5)(6)(7)(8). ATM is a key sensing protein involved in initiating DSB repair, as well as cellular growth and differentiation (22).…”

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Infection of a Single Cell Line with Distinct Strains of Human Cytomegalovirus Can Result in Large Variations in Virion Production and Facilitate Efficient Screening of Virus Protein Function

Zavala

O’Dowd

Fortunato

2016

J Virol

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Previously, we reported that the absence of the ataxia telangiectasia mutated (ATM) kinase, a critical DNA damage response (DDR) signaling component for double-strand breaks, caused no change in HCMV Towne virion production. Later, others reported decreased AD169 viral titers in the absence of ATM. To address this discrepancy, human foreskin fibroblasts (HFF) and three ATM ؊ lines (GM02530, GM05823, and GM03395) were infected with both Towne and AD169. Two additional ATM ؊ lines (GM02052 and GM03487) were infected with Towne. Remarkably, both previous studies' results were confirmed. However, the increased number of cell lines and infections with both lab-adapted strains confirmed that ATM was not necessary to produce wild-type-level titers in fibroblasts. Instead, interactions between individual virus strains and the cellular microenvironment of the individual ATM ؊ line determined efficiency of virion production. Surprisingly, these two commonly used lab-adapted strains produced drastically different titers in one ATM ؊ cell line, GM05823. The differences in titer suggested a rapid method for identifying genes involved in differential virion production. In silico comparison of the Towne and AD169 genomes determined a list of 28 probable candidates responsible for the difference. Using serial iterations of an experiment involving virion entry and input genome nuclear trafficking with a panel of related strains, we reduced this list to four (UL129, UL145, UL147, and UL148). As a proof of principle, reintroduction of UL148 largely rescued genome trafficking. Therefore, use of a battery of related strains offers an efficient method to narrow lists of candidate genes affecting various virus life cycle checkpoints. T he human cytomegalovirus (HCMV) life cycle involves a complex interplay between the virus and the host, with the virus exploiting the host cellular machinery for many of its own functions and, ultimately, releasing fully infectious virions. During a permissive HCMV infection, after virions have entered the cell, the tegument proteins and virus genome are independently trafficked to the nucleus. In fibroblasts, large bipolar viral replication centers (RCs) are formed within 48 h postinfection (hpi) and certain host cellular proteins become strongly associated with these RCs (1; reviewed in reference 2). These proteins include the regulatory protein p53 (3), as well as numerous components of the host cellular DNA damage response (DDR) and repair pathways (4-8).Many virus infections affect the DDR. The interactions span a range of up-and downregulations and include a complex dynamic between the virus and its host's damage response (as reviewed in references 6 and 9). Some viruses appear to require DDR proteins for efficient replication (10, 11), while for other viruses an efficient DDR can be detrimental to their DNA replication (12-21). Studies from several labs, including our own, have shown that HCMV infection initiates the ataxia telangiectasia mutated (ATM)-dependent double-strand break (DSB) ...

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Network representations of immune system complexity

Subramanian

Torabi‐Parizi

Gottschalk

et al. 2015

WIREs Mechanisms of Disease

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The mammalian immune system is a dynamic multi-scale system composed of a hierarchically organized set of molecular, cellular and organismal networks that act in concert to promote effective host defense. These networks range from those involving gene regulatory and protein-protein interactions underlying intracellular signaling pathways and single cell responses to increasingly complex networks of in vivo cellular interaction, positioning and migration that determine the overall immune response of an organism. Immunity is thus not the product of simple signaling events but rather non-linear behaviors arising from dynamic, feedback-regulated interactions among many components. One of the major goals of systems immunology is to quantitatively measure these complex multi-scale spatial and temporal interactions, permitting development of computational models that can be used to predict responses to perturbation. Recent technological advances permit collection of comprehensive datasets at multiple molecular and cellular levels while advances in network biology support representation of the relationships of components at each level as physical or functional interaction networks. The latter facilitate effective visualization of patterns and recognition of emergent properties arising from the many interactions of genes, molecules, and cells of the immune system. We illustrate the power of integrating ‘omics’ and network modeling approaches for unbiased reconstruction of signaling and transcriptional networks with a focus on applications involving the innate immune system. We further discuss future possibilities for reconstruction of increasingly complex cellular and organism-level networks and development of sophisticated computational tools for prediction of emergent immune behavior arising from the concerted action of these networks.

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HCMV-Infected Cells Maintain Efficient Nucleotide Excision Repair of the Viral Genome while Abrogating Repair of the Host Genome

Cited by 25 publications

References 76 publications

Viral and cellular subnuclear structures in human cytomegalovirus-infected cells

Viral and cellular subnuclear structures in human cytomegalovirus-infected cells

Infection of a Single Cell Line with Distinct Strains of Human Cytomegalovirus Can Result in Large Variations in Virion Production and Facilitate Efficient Screening of Virus Protein Function

Network representations of immune system complexity

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