Kaposi's Sarcoma-Associated Herpesvirus Transactivator Rta Induces Cell Cycle Arrest in G
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 /G
 1
 Phase by Stabilizing and Promoting Nuclear Localization of p27
 kip

Grand

2015

Viruses

With between 10% and 15% of human cancers attributable to viral infection, there is great interest, from both a scientific and clinical viewpoint, as to how these pathogens modulate host cell functions. Seven human tumour viruses have been identified as being involved in the development of specific malignancies. It has long been known that the introduction of chromosomal aberrations is a common feature of viral infections. Intensive research over the past two decades has subsequently revealed that viruses specifically interact with cellular mechanisms responsible for the recognition and repair of DNA lesions, collectively known as the DNA damage response (DDR). These interactions can involve activation and deactivation of individual DDR pathways as well as the recruitment of specific proteins to sites of viral replication. Since the DDR has evolved to protect the genome from the accumulation of deleterious mutations, deregulation is inevitably associated with an increased risk of tumour formation. This review summarises the current literature regarding the complex relationship between known human tumour viruses and the DDR and aims to shed light on how these interactions can contribute to genomic instability and ultimately the development of human cancers.

Section: Hepatitis B Virus (Hbv)mentioning

confidence: 99%

Modulation of DNA Damage and Repair Pathways by Human Tumour Viruses

Grand

2015

Viruses

“…It was notable that a G1 block was not observed during the first 24 h following lytic replication considering that this has been reported in several studies of herpesviruses including KSHV [ 21 , 36 , 37 , 38 , 39 ]. KSHV lytic proteins RTA and K8α have both been shown to induce a G1 block when expressed in isolation [ 37 , 38 , 39 ]. However, KSHV also encodes a D-cyclin homolog, known as v-cyclin, that has been reported to induce cell cycle progression via inactivation of p27 KIP1 [ 40 ].…”

Section: Discussionmentioning

confidence: 69%

Activation of DNA Damage Response Pathways during Lytic Replication of KSHV

Skalka

Stewart

et al. 2015

Viruses

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the causative agent of several human malignancies. Human tumour viruses such as KSHV are known to interact with the DNA damage response (DDR), the molecular pathways that recognise and repair lesions in cellular DNA. Here it is demonstrated that lytic reactivation of KSHV leads to activation of the ATM and DNA-PK DDR kinases resulting in phosphorylation of multiple downstream substrates. Inhibition of ATM results in the reduction of overall levels of viral replication while inhibition of DNA-PK increases activation of ATM and leads to earlier viral release. There is no activation of the ATR-CHK1 pathway following lytic replication and CHK1 phosphorylation is inhibited at later times during the lytic cycle. Despite evidence of double-strand breaks and phosphorylation of H2AX, 53BP1 foci are not consistently observed in cells containing lytic virus although RPA32 and MRE11 localise to sites of viral DNA synthesis. Activation of the DDR following KSHV lytic reactivation does not result in a G1 cell cycle block and cells are able to proceed to S-phase during the lytic cycle. KSHV appears then to selectively activate DDR pathways, modulate cell cycle progression and recruit DDR proteins to sites of viral replication during the lytic cycle.

“…Using a Cdt1-eGFP fusion protein to track cell-cycle progression in live cells containing lytic virus, the authors observed that EBV RCs develop in early S phase and sequester the PCNA DNA clamp while excluding cellular DNA and histones. Previous studies demonstrating that individual expression of the KSHV lytic proteins RTA and K8α results in G1 arrest have provided additional evidence that prevention of S-phase entry is an advantageous herpesvirus adaptation [4,5]. However, it is also known that V-cyclin, a KSHV d-type cyclin homologue expressed in both the latent and lytic phases, inactivates p27 promoting cell-cycle progression through G1 into S phase [24].…”

Section: Discussionmentioning

confidence: 99%

“…The proposed rationale was that, by restricting S-phase entry, the virus avoids competition with cellular DNA for replication resources. In support of these findings, both the KSHV immediate-early proteins RTA and K8α have been shown to negatively regulate the G1/S transition when expressed alone [4,5]. In contrast, another study presented evidence that S phase provides a more conducive environment for KSHV replication due to upregulation of genes that promote DNA replication, cell survival and lipid metabolism [6].…”

Section: Introductionmentioning

confidence: 87%

See 1 more Smart Citation

Productive herpesvirus lytic replication in primary effusion lymphoma cells requires S-phase entry

Journal of General Virology

Stewart

Grand

2020

Gammaherpesviruses establish lifelong latent infection in B lymphocytes and are the causative agent of several B-cell malignancies and lymphoproliferative disorders. While a quiescent latent infection allows these pathogens to evade immune detection, initiation of an alternative lifecycle stage, known as lytic replication, is an essential step in the production and dissemination of infectious progeny. Although cessation of cellular proliferation is an eventual consequence of lytic induction, exactly how gammaherpesviruses manipulate the cell cycle prior to amplification of viral DNA remains under debate. Here we show that the onset of Kaposi's sarcoma-associated herpesvirus (KSHV) lytic reactivation in B cells leads to S-phase accumulation and that exit from G1 is required for efficient viral DNA replication. We also show that lytic replication leads to an S-phase-specific activation of the DNA damage response (DDR) that is abrogated when lytic replication is restricted to G0/G1. Finally, we observe that expression of early lytic viral genes results in cellular replication stress with increased stalling of DNA replication forks. Overall, we demonstrate that S-phase entry is important for optimal KSHV replication, that G1 arresting compounds are effective inhibitors of viral propagation, and that lytic-induced cell-cycle arrest could occur through the obstruction of cellular replication forks and subsequent activation of the DDR.