RESUMO
Tumor viruses promote cell proliferation in order to gain access to an environment suitable for persistence and replication. The expression of viral products that promote growth transformation is often accompanied by the induction of multiple signs of telomere dysfunction, including telomere shortening, damage of telomeric DNA and chromosome instability. Long-term survival and progression to full malignancy require the bypassing of senescence programs that are triggered by the damaged telomeres. Here we review different strategies by which tumor viruses interfere with telomere homeostasis during cell transformation. This frequently involves the activation of telomerase, which assures both the integrity and functionality of telomeres. In addition, recent evidence suggests that oncogenic viruses may activate a recombination-based mechanism for telomere elongation known as Alternative Lengthening of Telomeres (ALT). This error-prone strategy promotes genomic instability and could play an important role in viral oncogenesis.
Assuntos
Vírus Oncogênicos/fisiologia , Telômero/genética , Telômero/metabolismo , Replicação Viral , Animais , Transformação Celular Viral , Senescência Celular/genética , Instabilidade Genômica , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/virologia , Infecções Tumorais por Vírus/genética , Infecções Tumorais por Vírus/metabolismo , Infecções Tumorais por Vírus/virologiaRESUMO
The Epstein-Barr virus (EBV) encoded nuclear antigen (EBNA)-1 regulates virus replication and transcription, and participates in the remodeling of the cellular environment that accompanies EBV induced B-cell immortalization and malignant transformation. The putative cellular targets of these effects of EBNA-1 are largely unknown. To address this issue we have profiled the transcriptional changes induced by short- and long-term expression of EBNA-1 in the EBV negative B-cell lymphoma BJAB. Three hundred and nineteen cellular genes were regulated in a conditional transfectant shortly after EBNA-1 induction while a ten fold higher number of genes was regulated upon continuous EBNA-1 expression. Promoter analysis of the differentially regulated genes demonstrated a significant enrichment of putative EBNA-1 binding sites suggesting that EBNA-1 may directly influence the transcription of a subset of genes. Gene ontology analysis of forty seven genes that were consistently regulated independently on the time of EBNA-1 expression revealed an unexpected enrichment of genes involved in the maintenance of chromatin architecture. The interaction network of the affected gene products suggests that EBNA-1 may promote a broad rearrangement of the cellular transcription landscape by altering the expression of key components of chromatin remodeling complexes.
Assuntos
Montagem e Desmontagem da Cromatina , Antígenos Nucleares do Vírus Epstein-Barr/genética , Perfilação da Expressão Gênica , Herpesvirus Humano 4 , Linhagem Celular Tumoral , Expressão Gênica , Humanos , Linfoma de Células B/genética , Linfoma de Células B/patologia , Linfoma de Células B/virologia , Nucleossomos/genética , Regiões Promotoras Genéticas/genética , Proteínas/metabolismo , TransfecçãoRESUMO
Epidemiological and molecular evidence links Epstein-Barr virus (EBV) carriage to the pathogenesis of human malignancies of lymphoid and epithelial cell origin but the mechanisms of viral oncogenesis are poorly understood. Burkitt's lymphoma, a tumor occurring in both EBV-positive and -negative forms, provides a convenient model for analysis of the relative contribution of genetic changes and viral products that are expressed in the malignant cells. Here we review recent findings that highlight several mechanisms by which EBV could play an important role in oncogenesis by promoting genomic instability.
Assuntos
Linfoma de Burkitt/virologia , Infecções por Vírus Epstein-Barr/virologia , Instabilidade Genômica , Herpesvirus Humano 4/fisiologia , Animais , HumanosRESUMO
The Epstein-Barr virus (EBV) nuclear antigen (EBNA)-1 is the only viral protein expressed in all EBV-carrying malignancies, but its contribution to oncogenesis has remained enigmatic. We show that EBNA-1 induces chromosomal aberrations, DNA double-strand breaks, and engagement of the DNA damage response (DDR). These signs of genomic instability are associated with the production of reactive oxygen species (ROS) and are reversed by antioxidants. The catalytic subunit of the leukocyte NADPH oxidase, NOX2/gp91(phox), is transcriptionally activated in EBNA-1-expressing cells, whereas inactivation of the enzyme by chemical inhibitors or RNAi halts ROS production and DDR. These findings highlight a novel function of EBNA-1 and a possible mechanism by which expression of this viral protein could contribute to malignant transformation and tumor progression.
