| Summary: | 碩士 === 國立臺灣大學 === 微生物學研究所 === 90 === Chromosome aberrations are closely related to tumor formation and it is believed that many oncogenic viruses such as HTLV-1 and HBV may induce cell transformation by interfering DNA repair machinery. Cytogenetic studies show that many chromosomal abnormalities were observed in the tissues of EBV-associated malignancies, and a report in 2001 also pointed out that the existence of EBV genome might increase micronucleus formation. These data suggest that EBV infection may enhance genomic instability and contribute to the carcinogenesis of EBV. In this study, we investigated the effect of three EBV gene products LMP1, EBNA1 and DNase on DNA repair, using host cell reactivation (HCR) assay.
LMP1 is an important oncogene of EBV, and can trigger numerous cellular signaling pathways, such as NF-kB, AP1, p38 and JAK/STAT cascades. In this study, expression of LMP-1 reduced the ability of DNA repair in both NPC-TW01 and H1299 cell lines, indicating that reduction of DNA repair by LMP-1 may through both p53-dependent and p53-independent pathways. To determine which domain is important for reducing DNA repair, different LMP-1 deletion mutants were measured. Our data show that LMP1 mutant (D189-222) partially lost its ability to reduce DNA repair and indicates that CTAR1 domain is important for LMP-1 to interfere DNA repair.
EBNA1 is important for EBV immortalization. It is responsible for viral genome replication and maintenance during latent stage, and also regulates the expression of other latent genes. In metaphase, EBNA1 can bind to condensed chromosome through cellular proteins. In our study, EBNA1 does not affect DNA repair either in NPC-TW01 or in H1299 cell lines by using HCR assay.
DNase, a nuclease, is able to cleave single- and double- stranded DNA and was reported to induce gene mutation and micronucleus formation. In this study, expression of DNase enhances DNA repair in NPC-TW01 and H1299 cell lines, indicating that DNase may damage DNA and result in increase of cellular DNA repair.
Based on these results, we suggest that two EBV viral protein LMP1 and DNase may affect DNA repair and promote chromosome alterations so that EBV infection may predispose cells to accumulate damaged DNA and contribute to tumor development.
|
|---|
