Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic herpesvirus associated with multiple AIDS-related malignancies. Like other herpesviruses, KSHV has a biphasic life cycle and both the lytic and latent phases are required for tumorigenesis. Evidence suggests that KSHV lytic replication can cause genome instability in KSHV-infected cells, although no mechanism has thus far been described. A surprising link has recently been suggested between mRNA export, genome instability and cancer development. Notably, aberrations in the cellular transcription and export complex (hTREX) proteins have been identified in high-grade tumours and these defects contribute to genome instability. We have previously shown that the lytically expressed KSHV ORF57 protein interacts with the complete hTREX complex; therefore, we investigated the possible intriguing link between ORF57, hTREX and KSHV-induced genome instability. Herein, we show that lytically active KSHV infected cells induce a DNA damage response and, importantly, we demonstrate directly that this is due to DNA strand breaks. Furthermore, we show that sequestration of the hTREX complex by the KSHV ORF57 protein leads to this double strand break response and significant DNA damage. Moreover, we describe a novel mechanism showing that the genetic instability observed is a consequence of R-loop formation. Importantly, the link between hTREX sequestration and DNA damage may be a common feature in herpesvirus infection, as a similar phenotype was observed with the herpes simplex virus 1 (HSV-1) ICP27 protein. Our data provide a model of R-loop induced DNA damage in KSHV infected cells and describes a novel system for studying genome instability caused by aberrant hTREX.
Highlights
Genome instability, an enabling characteristic of the hallmarks of cancer, has long been established as a major contributing factor to cancer formation and progression [1,2]
This study demonstrated that H2A.x is phosphorylated during Kaposi’s sarcoma-associated herpesvirus (KSHV) latency, confirmed by our western blot analysis (Figure 1B), but our data convincingly show that this level is dramatically increased during the KSHV lytic replication cycle
We set out to investigate what effect sequestration of Human TREX (hTREX) by KSHV open reading frame 57 (ORF57) would have upon R-loop formation and genome instability, and whether this would describe a mechanism by which KSHV could induce DNA strand-breaks
Summary
An enabling characteristic of the hallmarks of cancer, has long been established as a major contributing factor to cancer formation and progression [1,2]. Contributing factors of genome instability are wide ranging and incorporate those from exogenous sources, such as ionising radiation, endogenous sources such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), as well as mutations incorporated into the genome during cell replication, including DNA replication errors and error prone DNA repair [3,4]. The most severe types of DNA damage result in double strand breaks (DSB) that can be repaired primarily through error-free homologous recombination (HR) [5,6], or error-prone non-homologous end-joining (NHEJ) [6]. DSBs are known to be an integral part of many cancers, for example, breast cancers, Burkitt’s lymphoma, and multiple leukaemia’s [10,11,12]
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