A Novel Mechanism Inducing Genome Instability in Kaposi's Sarcoma-Associated Herpesvirus Infected Cells

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The hallmarks of cancer comprise the essential elements that permit the formation and development of human tumours. Genome instability is an enabling characteristic that allows the progression of tumorigenesis through genetic mutation and therefore, understanding the molecular causes of genome instability in all cancers is essential for development of therapeutics. The Kaposi's sarcoma-associated herpesvirus (KSHV) is an important human pathogen that causes multiple AIDS-related cancers. Recent studies have shown that during KSHV infection, cells show an increase in a double-strand DNA break marker, signifying a severe form of genome instability. Herein, we show that KSHV infection does cause DNA strand breaks. Moreover, we describe a novel molecular mechanism for genome instability involving the KSHV ORF57 protein interacting with the mRNA export complex, hTREX. We demonstrate that over-expression of ORF57 results in the formation of RNA:DNA hybrids, or R-loops, that lead to an increase in genome instability. DNA strand breaks have been previously reported in herpes simplex, cytomegalovirus and Epstein-Barr virus infected cells. Therefore, as this work describes for the first time the mechanism of R-loop induced genome instability involving a conserved herpesvirus protein, it may have far-reaching implications for other viral RNA export factors.

Vyšlo v časopise: A Novel Mechanism Inducing Genome Instability in Kaposi's Sarcoma-Associated Herpesvirus Infected Cells. PLoS Pathog 10(5): e32767. doi:10.1371/journal.ppat.1004098
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004098

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