Activation of DNA Damage Response Induced by the Kaposi's Sarcoma-Associated Herpes Virus

Abstract

The human herpes virus 8 (HHV-8), also known as Kaposi sarcoma-associated herpes virus (KSHV), can infect endothelial cells often leading to cell transformation and to the development of tumors, namely Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and the plasmablastic variant of multicentric Castleman's disease. KSHV is prevalent in areas such as sub-Saharan Africa and the Mediterranean region presenting distinct genotypes, which appear to be associated with differences in disease manifestation, according to geographical areas. In infected cells, KSHV persists in a latent episomal form. However, in a limited number of cells, it undergoes spontaneous lytic reactivation to ensure the production of new virions. During both the latent and the lytic cycle, KSHV is programmed to express genes which selectively modulate the DNA damage response (DDR) through the activation of the ataxia telangiectasia mutated (ATM) pathway and by phosphorylating factors associated with the DDR, including the major tumor suppressor protein p53 tumor suppressor p53. This review will focus on the interplay between the KSHV and the DDR response pathway throughout the viral lifecycle, exploring the putative molecular mechanism/s that may contribute to malignant transformation of host cells.

Keywords: DNA damage response; cancer; kaposi; sarcoma; skin; tumor.

Figure 1

Schematic representation of latency-associated nuclear antigen (LANA)-mediated Kaposi sarcoma-associated herpes virus (KSHV) episomal persistence after infection. LANA binds to LANA binding sequences in the episome terminal repeats by its C terminal region. In this model, γH2AX participates in KHSV episomal persistence possibly by strengthening the interaction between C-LANA and terminal repeat (TR) as proposed by Jha et al., 2013 [45].

Figure 2

LANA and the interacting factors involved in the DNA Damage induction as reported in the text.

Figure 3

Genome instability and DNA damage induction by the KSHV ORF57 as proposed by Jackson et al. 2014 [118]. In a healthy cell, the evolutionarily conserved multiprotein complex hTREX plays a major role during biogenesis and stabilization of the newly transcribed mRNA.