Open chromatin structures regulate the efficiencies of pre-RC formation and replication initiation in Epstein-Barr virus

Papior, Peer; Arteaga-Salas, José M.; Guenther, Thomas; Grundhoff, Adam; Schepers, Aloys

doi:10.1083/jcb.201109105

Cited by 16 publications

(31 citation statements)

References 64 publications

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“…Lee et al, 2012;Papior, Arteaga-Salas, Gunther, Grundhoff, & Schepers, 2012). Mammalian replication is tightly regulated by a process called replication licensing that is modulated by the cell cycle and ensures that replication occurs once per cycle (Sclafani & Holzen, 2007;Truong & Wu, 2011).…”

Section: Papillomavirus Replicationmentioning

confidence: 99%

Human Papillomavirus Replication Regulation by Acetylation of a Conserved Lysine in the E2 Protein

Thomas

Androphy

2018

J Virol

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iii ACKNOWLEDGEMENTS I would like to thank my supervisor Elliot J. Androphy for his guidance, and encouragement over these many years. I truly appreciate your faith and continuous support.I also want to thank all members of the Androphy lab, for your guidance, critiques, and support.Thank you to my thesis committee, without whom none of this would be possible.Your guidance has been invaluable. Michael Klemsz, Suk-Hee Lee, Lindsey Mayo, and Andy Yu. The Papillomavirus E2 protein is a sequence specific DNA binding protein that recruits cellular factors to its genome in infected epithelial cells. E2 also binds to and loads the viral E1 DNA helicase at the origin of replication. Post-translational modifications of PV E2 have been identified as potential regulators of E2 functions. We recently reported lysine (K) 111 as a target of p300 acetylation in B(bovine)PV that is involved in the regulation of viral transcription. K111 is conserved in most papillomaviruses, so we pursued a mutational approach to query the functional significance of lysine in HPV E2. Amino acid substitutions that prevent acetylation, including arginine, were unable to stimulate transcription and E1 mediated DNA replication. The arginine K111 mutant retained E2 transcriptional repression, nuclear localization, DNA and chromatin binding, and association with E2 binding partners involved in PV transcription and replication. v When directly investigating origin unwinding, the replication defective E2 K111R mutant recruited E1 to the viral replication origin, but surprisingly, unwinding of the duplex DNA did not occur. In contrast, the glutamine K111 mutant increased origin melting and stimulated replication compared to wild type E2. We have identified Topoisomerase I as a key host factor involved in viral replication whose recruitment is dependent on K111 acetylation, and propose a new model for viral origin dynamics during replication initiation. This work reveals a novel activity of E2 necessary for denaturing the viral origin that likely depends on acetylation of highly conserved lysine 111. Human Papillomaviruses and DiseaseThere are over 200 HPVs that have been described and they manifest in a variety of ways; they can be asymptomatic, or they can result in benign lesions (papillomas) or progress to malignancy (de Villiers, Fauquet, Broker, Bernard, & zur Hausen, 2004). In the United States, HPV is the most common sexually transmitted infection and nearly all sexually active adults contract it at least once. E1The PV E1 protein is an essential viral replication factor (Lusky & Botchan, 1985;Ustav, Ustav, Szymanski, & Stenlund, 1991). E1 is the viral helicase and initiates replication by binding to specific sequences on the viral genome with the assistance of the E2 protein (Frattini & Laimins, 1994).There is sequence and functional homology between PV E1 and SV (simian virus) 40 Large T Antigen which allowed for many of the predictions concerning E2 shows differential affinity for the E2BS and it is proposed that at low levels, E2b...

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Section: Papillomavirus Replicationmentioning

confidence: 99%

Human Papillomavirus Replication Regulation by Acetylation of a Conserved Lysine in the E2 Protein

Thomas

Androphy

2018

J Virol

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“…Interestingly, ORC binding sites are partially linked with patterns of gene expression [25,26]. One reason is that both transcriptional active promoters and DNA replication origins require a stretch of nucleosome-free DNA [27][28][29]. AT-or G-rich sequences promote nucleosome exclusion and are enriched at origins.…”

Section: Dna Replication Originsmentioning

confidence: 98%

Helicase loading: How to build a MCM2-7 double-hexamer

Riera

Tognetti

Speck

2014

Seminars in Cell & Developmental Biology

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“…With its defined origin sequence (oriP) and replication factors, it has become a powerful tool to study the initiation process of eukaryotic DNA replication [101–105]. As the cellular mechanisms unfold, one can develop effective targeted therapy to eradicate the EBV latency.…”

Section: Epstein–barr Virus (Ebv): Taking Advantage Of Host Orcmentioning

confidence: 99%

The origin recognition complex in human diseases

Shen

2013

Bioscience Reports

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ORC (origin recognition complex) serves as the initiator for the assembly of the pre-RC (pre-replication complex) and the subsequent DNA replication. Together with many of its non-replication functions, ORC is a pivotal regulator of various cellular processes. Notably, a number of reports connect ORC to numerous human diseases, including MGS (Meier–Gorlin syndrome), EBV (Epstein–Barr virus)-infected diseases, American trypanosomiasis and African trypanosomiasis. However, much of the underlying molecular mechanism remains unclear. In those genetic diseases, mutations in ORC alter its function and lead to the dysregulated phenotypes; whereas in some pathogen-induced symptoms, host ORC and archaeal-like ORC are exploited by these organisms to maintain their own genomes. In this review, I provide detailed examples of ORC-related human diseases, and summarize the current findings on how ORC is involved and/or dysregulated. I further discuss how these discoveries can be generalized as model systems, which can then be applied to elucidating other related diseases and revealing potential targets for developing effective therapies.

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Open chromatin structures regulate the efficiencies of pre-RC formation and replication initiation in Epstein-Barr virus

Abstract: Studies of EBV replication origins demonstrate an excess of pre-replication complexes that are formed at flexible MNase-sensitive sites in the genome.

Cited by 16 publications

References 64 publications

Human Papillomavirus Replication Regulation by Acetylation of a Conserved Lysine in the E2 Protein

Human Papillomavirus Replication Regulation by Acetylation of a Conserved Lysine in the E2 Protein

Helicase loading: How to build a MCM2-7 double-hexamer

The origin recognition complex in human diseases

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