Volume 7 Supplement 1

Proceedings of the 13th International Conference on Malignancies in AIDS and Other Acquired Immunodeficiencies (ICMAOI)

Open Access

Herpesviruses control the DNA damage response through TIP60

  • Renfeng Li1Email author,
  • Jian Zhu2, 3,
  • Zhi Xie4,
  • Gangling Liao1,
  • Shaohui Hu2, 3,
  • Crystal Woodard2, 3,
  • Jimmy Lin1,
  • Gary S Hayward1, 2, 5,
  • Jiang Qian1, 4, 5,
  • Heng Zhu1, 2, 3, 5 and
  • S Diane Hayward1, 2, 5
Infectious Agents and Cancer20127(Suppl 1):O8

https://doi.org/10.1186/1750-9378-7-S1-O8

Published: 19 April 2012

Background and results

Herpesviruses establish life-long persistent infections that result in clinical manifestations ranging from mild cold sores, to pneumonitis and cancers. Immunosuppressed populations, including AIDS patients, are at risk for more serious disease outcomes. Although the α-, β-, and γ-herpesviruses infect different tissues and cause distinct diseases, they confront many of the same challenges in producing new virions and spreading infection. The herpesvirus families each encode a conserved serine/threonine kinase that plays an important role in virus replication and spread. Despite the potential of these kinases as pharmacological targets, the extent of substrate conservation and the key common cell signalling pathways targeted by these enzymes are unknown. We applied a human protein microarray, high-throughput approach to identifying shared substrates of the conserved kinases from herpes simplex virus, human cytomegalovirus, Epstein-Barr virus (EBV) and Kaposi’s sarcoma associated herpesvirus. We identified 110 shared host substrates targeted by at least three conserved viral kinases. Bioinformatics analyses revealed that proteins involved in the DNA damage response (DDR) were statistically enriched and further orthogonal analysis led to an in-depth characterization of a histone acetyltransferase, TIP60, as a master regulator that is exploited by these viruses. In EBV replication, TIP60 acts both by triggering the EBV-induced DDR and by regulating expression of viral lytic genes (Figure 1).
Figure 1

:

Conclusions

1. The conserved herpesvirus kinases target the DNA damage response (DDR) pathway.

2. The EBV kinase BGLF4 induces the DDR and regulates key lytic viral genes through TIP60.

3. TIP60 knockdown impairs and γ herpesvirus replication.

4. Identification of key cellular targets of the conserved herpesvirus kinases will facilitate the development of broadly effective anti-viral strategies.

Authors’ Affiliations

(1)
Department of Oncology, Johns Hopkins School of Medicine
(2)
Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine
(3)
High Throughput Biology Center, Johns Hopkins School of Medicine
(4)
Department of Ophthalmology, Johns Hopkins School of Medicine
(5)
Kimmel Cancer Center, Johns Hopkins School of Medicine

Copyright

© Li et al; licensee BioMed Central Ltd. 2012

This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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