DNA damage response confers a barrier for viral tumorigenesis

September 27, 2007

Kaposi's sarcoma herpesvirus (KSHV) is a human tumor virus and an etiological agent for Kaposi's sarcoma (KS). KSHV infection is endemic in sub-Saharan Africa where KS is nowadays the most common malignancy, due to widespread infection with KSHV and human immunodeficiency virus (HIV). Importantly, KS also occurs in HIV-negative individuals. Researchers at the University of Helsinki, Finland, have discovered that activation of the DNA damage response in the early stages of KS development functions as an anti-cancer barrier also in virus induced malignancies.

Recent findings suggest that DNA damage checkpoints become activated in early stages of human tumorigenesis, leading to growth arrest or apoptosis and thereby hindering tumor progression. DNA hyper-replication triggered by oncogenes can induce cellular senescence, which together with the oncogene-induced DNA damage checkpoint function as an early anti-cancer barrier. The findings by the research group of Päivi Ojala, Ph.D., (University of Helsinki) demonstrate that the DNA damage checkpoint is activated during the initial stages of KSHV infection and KS tumorigenesis and this can confer a barrier to tumorigenesis also in virus induced cancers.

The study will be published 28.9.2007 in Public Library of Science (PLoS) Pathogens.

KSHV displays two patterns of infection: latent and lytic phase. During latency, only a restricted set of viral genes is expressed. The KSHV genome encodes several homologues of cellular proteins, which engage cellular signaling pathways, govern cell proliferation and modulate apoptosis. The results of this study demonstrate that one of the viral latent proteins, viral cyclin, which is a homolog of cellular D-type cyclins, induces replicative stress in endothelial cells, which leads to senescence and activation of the DNA damage response.

To support the finding early stage lesions of clinical KS specimens were analysed in the study. The results demonstrate that DNA damage checkpoint is activated in early, but not late stage lesions of clinical KS specimens. During the course of infection, the KSHV infected cells may be imposed to overcome this checkpoint, and oncogenic stress elicited by the expression of the viral cyclin may further contribute to the induction of genomic instability and malignant transformation.
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The project involves scientists from two Academy of Finland National Centre of Excellence Programs, the Translational Genome-Scale Biology and Cancer Biology, and involved collaboration with the groups of professor Marikki Laiho (University of Helsinki), professor Kari Alitalo (University of Helsinki), and professor Peter Biberfeld (Karolinska Institute). This work was supported by grants from the Academy of Finland including also Centres of Excellence in Translational Genome-Scale Biology and Cancer Biology, and additional funds have been obtained from the University of Helsinki, Academy of Finland research program for Systems Biology and Bioinformatics, TEKES, Finnish Cancer Foundations, Sigrid Jusélius Foundation, and from the European Union (FP6 INCA project LSHC-CT-2005-018704).

Reference: Koopal, S., Furuhjelm, J.H., Järviluoma, A., Jäämaa, S., Pyakurel, P., Pussinen, C., Wirzenius, M., Biberfeld, P., Alitalo, K., Laiho, M., and Ojala, P.M. 2007: Viral oncogene-induced DNA damage response is activated in Kaposi's sarcoma tumorigenesis. PLoS Pathogens.

University of Helsinki

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