Interaction of herpes simplex virus 1 origin-binding protein with DNA polymerase alpha.

Lee, Sam S.-K.; Dong, Qun; Wang, T. S. F.; Lehman, I. R.

doi:10.1073/pnas.92.17.7882

Cited by 24 publications

(13 citation statements)

References 30 publications

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“…Moreover, cdk-2-mediated phosphorylation of proteins that regulate DNA replication, such as HsCdc6, is also required for cellular DNA replication (40). Finally, the expression of many enzymes required for cellular DNA replication (including DNA ligase 1 and DNA Pol ␣) is dependent on cdk-2 activity (18,52), and, as noted above, some of these cellular proteins may also be required for HSV DNA synthesis (27,46,50,75).…”

Section: Discussionmentioning

confidence: 99%

“…Of these proteins, DNA ligase 1 may serve to circularize the viral genome, an event required for viral DNA synthesis (5). Cellular DNA Pol ␣ interacts with, and is activated by, the HSV origin binding protein (50). Topoisomerase II (p170) has been reported to be involved in viral DNA replication, since inhibition of this cellular enzyme results in some inhibition of HSV DNA synthesis (27).…”

Section: Discussionmentioning

confidence: 99%

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Roscovitine, a Specific Inhibitor of Cellular Cyclin-Dependent Kinases, Inhibits Herpes Simplex Virus DNA Synthesis in the Presence of Viral Early Proteins

Schang

Rosenberg

Schaffer

2000

J Virol

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We have previously shown that two inhibitors specific for cellular cyclin-dependent kinases (cdks), Roscovitine (Rosco) and Olomoucine (Olo), block the replication of herpes simplex virus (HSV). Based on these results, we demonstrated that HSV replication requires cellular cdks that are sensitive to these drugs (L. M. Schang, J. Phillips, and P. A. Schaffer. J. Virol. 72:5626-5637, 1998). We further established that at least two distinct steps in the viral replication cycle require cdks: transcription of immediate-early (IE) genes and transcription of early (E) genes (L. M. Schang, A. Rosenberg, and P. A. Schaffer, J. Virol. 73:2161-2172, 1999). Since Rosco inhibits HSV replication efficiently even when added to infected cells at 6 h postinfection, we postulated that cdks may also be required for viral functions that occur after E gene expression. In the study presented herein, we tested this hypothesis directly by measuring the efficiency of viral replication, viral DNA synthesis, and expression of several viral genes during infections in which Rosco was added after E proteins had already been synthesized. Rosco inhibited HSV replication, and specifically viral DNA synthesis, when the drug was added at the time of release from a 12-h phosphonoacetic acid (PAA)-induced block in viral DNA synthesis. Inhibition of DNA synthesis was not a consequence of inhibition of expression of IE or E genes in that Rosco had no effect on steady-state levels of two E transcripts under the same conditions in which it inhibited viral DNA synthesis. Moreover, viral DNA synthesis was inhibited by Rosco even in the absence of protein synthesis. In a second series of experiments, the replication of four HSV mutants harboring temperature-sensitive mutations in genes essential for viral DNA replication was inhibited when Rosco was added at the time of shift-down from the nonpermissive to the permissive temperature. Viral DNA synthesis was inhibited by Rosco under these conditions, whereas expression of viral E genes was not affected. We conclude that cellular Rosco-sensitive cdks are required for replication of viral DNA in the presence of viral E proteins. This requirement may indicate that HSV DNA synthesis is functionally linked to transcription, which requires cdks, or that both viral transcription and DNA replication, independently, require viral or cellular factors activated by Rosco-sensitive cdks.Herpes simplex virus (HSV) replicates in both cycling and noncycling cells, including terminally differentiated neurons. HSV replication, however, requires cellular functions associated with cell cycle progression. Thus, HSV replicates more efficiently in actively dividing than growth-arrested cells. This difference in replication efficiency is especially prominent among viral mutants which lack specific viral functions such as those provided by the regulatory proteins ICP0 and VP16 or by enzymes involved in nucleotide metabolism, such as thymidine kinase (TK) or ribonucleotide reductase (9, 16, 25). The dependence on cell cycle-activat...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Roscovitine, a Specific Inhibitor of Cellular Cyclin-Dependent Kinases, Inhibits Herpes Simplex Virus DNA Synthesis in the Presence of Viral Early Proteins

Schang

Rosenberg

Schaffer

2000

J Virol

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“…Two other observations, however, provide support for the possible involvement of pol ␣. First, Lehman and co-workers (51) demonstrated that UL9, the HSV-1 origin-binding protein, interacts with pol ␣, thus providing a potential mechanism to recruit pol ␣ to initiation sites. Second, immunofluorescence studies indicate that herpes replication compartments contain pol ␣ (52).…”

Section: Discussionmentioning

confidence: 99%

Initiation of New DNA Strands by the Herpes Simplex Virus-1 Primase-Helicase Complex and Either Herpes DNA Polymerase or Human DNA Polymerase α

Cavanaugh

Kuchta

2009

Journal of Biological Chemistry

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A key set of reactions for the initiation of new DNA strands during herpes simplex virus-1 replication consists of the primase-catalyzed synthesis of short RNA primers followed by polymerase-catalyzed DNA synthesis (i.e. primase-coupled polymerase activity). Herpes primase (UL5-UL52-UL8) synthesizes products from 2 to ϳ13 nucleotides long. However, the herpes polymerase (UL30 or UL30-UL42) only elongates those at least 8 nucleotides long. Surprisingly, coupled activity was remarkably inefficient, even considering only those primers at least 8 nucleotides long, and herpes polymerase typically elongated <2% of the primase-synthesized primers. Of those primers elongated, only 4 -26% of the primers were passed directly from the primase to the polymerase (UL30-UL42) without dissociating into solution. Comparing RNA primer-templates and DNA primertemplates of identical sequence showed that herpes polymerase greatly preferred to elongate the DNA primer by 650 -26,000-fold, thus accounting for the extremely low efficiency with which herpes polymerase elongated primase-synthesized primers. Curiously, one of the DNA polymerases of the host cell, polymerase ␣ (p70-p180 or p49-p58-p70-p180 complex), extended herpes primase-synthesized RNA primers much more efficiently than the viral polymerase, raising the possibility that the viral polymerase may not be the only one involved in herpes DNA replication.Herpes simplex virus 1 (HSV-1) 2 encodes seven proteins essential for replicating its double-stranded DNA genome; five of these encode the heterotrimeric helicase-primase (UL5-UL52-UL8 gene products) and the heterodimeric polymerase (UL30-UL42 gene products) (1, 2). The helicase-primase unwinds the DNA at the replication fork and generates singlestranded DNA for both leading and lagging strand synthesis. Primase synthesizes short RNA primers on the lagging strand that the polymerase presumably elongates using dNTPs (i.e. primase-coupled polymerase activity). These two protein complexes are thought to replicate the viral genome on both the leading and lagging strands (1, 2).Previous studies have focused on the helicase-primase and polymerase separately. The helicase-primase contains three subunits, UL5, UL52, and UL8 in a 1:1:1 ratio (3-5). The UL5 subunit has helicase-like motifs and the UL52 subunit has primase-like motifs, yet the minimal active complex that demonstrates either helicase or primase activities contains both UL5 and UL52 (6, 7). Although the UL8 subunit has no known catalytic activity, several functions have been proposed, including enhancing helicase and primase activities, enhancing primer synthesis on ICP8 (the HSV-1 single-stranded binding protein)-coated DNA strands, and facilitating formation of the replisome (8 -12). Although primase will synthesize short (2-3 nucleotides long) primers on a variety of template sequences, synthesis of longer primers up to 13 nucleotides long requires the template sequence, 3Ј-deoxyguanidine-pyrimidine-pyrimidine-5Ј (13). Primase initiates synthesis at the first pyrimidine...

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“…The key role for AR in diabetic cataractogenesis is further supported by studies in AR-overexpressing mice. Sugar cataracts form in transgenic diabetic mice expressing human AR in the lens, but not in wild-type streptozotocin-induced diabetic mice which have very low expression of AR (Varma and Kinoshita, 1974; Lee et al, 1995). AR siRNA transfection and inhibition suppressed high glucose-induced ROS formation, NF-kappaB activation, and apoptosis in rat lens epithelial cells (Nambu et al, 2008).…”

Section: Aldose Reductase and Other Complications In Diabetesmentioning

confidence: 99%

Aldose Reductase, Oxidative Stress, and Diabetic Mellitus

Tang¹,

Martin²,

Hwa³

2012

Front. Pharmacol.

349

229

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Diabetes mellitus (DM) is a complex metabolic disorder arising from lack of insulin production or insulin resistance (Diagnosis and classification of diabetes mellitus, 2007). DM is a leading cause of morbidity and mortality in the developed world, particularly from vascular complications such as atherothrombosis in the coronary vessels. Aldose reductase (AR; ALR2; EC 1.1.1.21), a key enzyme in the polyol pathway, catalyzes nicotinamide adenosine dinucleotide phosphate-dependent reduction of glucose to sorbitol, leading to excessive accumulation of intracellular reactive oxygen species (ROS) in various tissues of DM including the heart, vasculature, neurons, eyes, and kidneys. As an example, hyperglycemia through such polyol pathway induced oxidative stress, may have dual heart actions, on coronary blood vessel (atherothrombosis) and myocardium (heart failure) leading to severe morbidity and mortality (reviewed in Heather and Clarke, 2011). In cells cultured under high glucose conditions, many studies have demonstrated similar AR-dependent increases in ROS production, confirming AR as an important factor for the pathogenesis of many diabetic complications. Moreover, recent studies have shown that AR inhibitors may be able to prevent or delay the onset of cardiovascular complications such as ischemia/reperfusion injury, atherosclerosis, and atherothrombosis. In this review, we will focus on describing pivotal roles of AR in the pathogenesis of cardiovascular diseases as well as other diabetic complications, and the potential use of AR inhibitors as an emerging therapeutic strategy in preventing DM complications.

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Interaction of herpes simplex virus 1 origin-binding protein with DNA polymerase alpha.

Cited by 24 publications

References 30 publications

Roscovitine, a Specific Inhibitor of Cellular Cyclin-Dependent Kinases, Inhibits Herpes Simplex Virus DNA Synthesis in the Presence of Viral Early Proteins

Roscovitine, a Specific Inhibitor of Cellular Cyclin-Dependent Kinases, Inhibits Herpes Simplex Virus DNA Synthesis in the Presence of Viral Early Proteins

Initiation of New DNA Strands by the Herpes Simplex Virus-1 Primase-Helicase Complex and Either Herpes DNA Polymerase or Human DNA Polymerase α

Aldose Reductase, Oxidative Stress, and Diabetic Mellitus

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