Induction of Micronuclei by HTLV-I Tax: A Cellular Assay for Function

Majone, Franca; Semmes, O. John; Jeang, Kuan‐Teh

doi:10.1006/viro.1993.1145

Cited by 87 publications

(90 citation statements)

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“…This is an important feature of Tax's e ect on DNA repair because, if Tax suppression of DNA repair leads to an accumulation of DNA mutations, as our model predicts, it will likely require long term Tax expression to see this e ect. This ®nding is consistent with other reports suggesting that Tax expression promotes an accumulation of DNA damage (Majone et al, 1993;Saggioro et al, 1994;Miyake et al, 1999), and that HTLV-1 transformed cells exhibit various chromosomal abnormalities (Fujita et al, 1989;Kamada et al, 1992). It is not likely that Tax directly induces mutations, but rather that Tax suppresses repair of DNA damage resulting from other sources.…”

Section: Discussionsupporting

confidence: 92%

“…This evidence includes induction of micronuclei in Tax transfected cells (Majone et al, 1993;Saggioro et al, 1994) and enhanced mutation frequency of the cellular genome in Tax-expressing cells (Miyake et al, 1999). These e ects could result either directly from Tax stimulating DNA damage, or indirectly from Tax inhibiting repair of naturally occurring DNA damage.…”

Section: Introductionmentioning

confidence: 99%

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HTLV-1 Tax protein sensitizes cells to apoptotic cell death induced by DNA damaging agents

2000

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Transient HTLV-1 Tax expression suppresses cellular nucleotide excision repair, and this e ect correlates with Tax transactivation of the proliferating cell nuclear antigen promoter. The inability to repair DNA damage typically induces apoptotic cell death. Therefore, we investigated the e ect of Tax-mediated suppression of DNA repair on apoptosis in stable Tax-expressing cells. Constitutive Tax expression reduced cellular nucleotide excision repair activity compared with parental and control cells. Tax-expressing cells were also more sensitive to apoptosis induced by DNA damaging agents than control cells. Even though Tax-expressing cells displayed reduced DNA repair, they showed increased DNA replication following UV damage. These results suggest that Tax suppresses the cell's ability to repair DNA damage and stimulates DNA replication even in the presence of damage. The inability to repair DNA damage is likely to stimulate apoptotic cell death in the majority of Tax-expressing cells while the ability to promote DNA replication may also allow the survival of a small population of cells. We propose that together these e ects contribute to the monoclonal nature and low e ciency of HTLV-1 transformation.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

HTLV-1 Tax protein sensitizes cells to apoptotic cell death induced by DNA damaging agents

2000

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“…Since Tax is the major HTLV-I oncoprotein, it is reasonable to suggest that Tax has a critical impact on the integrity and stability of the cellular genome. An association between Tax expression and the presence of DNA damage was first demonstrated using micronucleus formation assays (Majone et al, 1993). Micronuclei formed by condensation of chromosomal fragments or whole chromosomes as a result of chromosome damage, exist in the cytoplasm, separate from the nuclei of daughter cells (Parry and Parry, 1987;Thomson and Perry, 1988).…”

Section: Effect Of Tax On Micronuclei Formation and Genome Stabilitymentioning

confidence: 99%

“…Saggioro et al (1994) showed that Tax transfected cells not only had more micronuclei than nontransfected cells, but also were more sensitive to mitomycin C (MMC) induced DNA damage. Tax expression has been associated with increased formation of micronuclei with free 3 0 -hydroxyl ends (Majone et al, 1993;Semmes et al, 1996) and these 3 0 DNA ends were accessible to labeling (Majone and Jeang, 2000), suggesting that they were not protected by telomere addition. This result is consistent with the studies described above showing reduced telomerase expression in mitogenically active Tax-expressing cells.…”

Section: Effect Of Tax On Micronuclei Formation and Genome Stabilitymentioning

confidence: 99%

Impact of HTLV-I Tax on cell cycle progression and the cellular DNA damage repair response

2005

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“…Among the human tumor viruses, HPV E6, HTLV1 Tax and HBV HBx disrupt p53-dependent transcriptional activity through distinct mechanisms and repress DNA repair and induce genomic instability, which contribute to viral oncogenesis (Scheffner et al, 1990;Majone et al, 1993;Lee et al, 1995;Smith et al, 1995;Truant et al, 1995;Akagi et al, 1997;Kao and Marriott, 1999;Philpott and Buehring, 1999). Thus, it seems common for viruses to contribute to carcinogenesis by repressing the activities of p53.…”

Section: Introductionmentioning

confidence: 99%

Epstein–Barr virus latent membrane protein 1 represses p53-mediated DNA repair and transcriptional activity

et al. 2004

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The latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV), a viral oncogene, is essential for transformation of resting B cells by the virus. We previously demonstrated that LMP1 could repress DNA repair in p53-wild-type and p53-deficient human epithelial cells. In this study, using a host cell reactivation (HCR) assay, we demonstrated that p53-enhanced DNA repair was repressed by LMP1 in p53-deficient cells. Moreover, we found that LMP1 was able to repress p53-dependent transcriptional activity. Regarding the mechanisms of p53 repression by LMP1, we found that LMP1 did not inhibit p53 function through direct interaction, by promoting protein degradation or reducing its DNA-binding ability. Using chimeric proteins in the reporter assay, we demonstrated that LMP1 inhibited p53 transactivation by influencing the N-terminal transactivation domain of p53. Subsequent experiments using various LMP1 deletion mutants indicated that a C-terminus-activating region of LMP1, CTAR1 or CTAR2, is responsible for the repression of p53-mediated DNA repair and p53-dependent transcription, which is correlated with the region responsible for NF-jB activation. Furthermore, blockage of NF-jB signalling by IjB-DN was shown to abolish the repression of p53 by LMP1, suggesting that LMP1 likely repressed p53 function through the NF-jB pathway. Based on these results, we propose that inhibition of p53-dependent transcriptional activity and DNA repair by LMP1 results in the loss of p53 activity for maintaining genomic stability, which may contribute to the oncogenesis of LMP1 in human epithelial cells.

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Induction of Micronuclei by HTLV-I Tax: A Cellular Assay for Function

Cited by 87 publications

References 0 publications

HTLV-1 Tax protein sensitizes cells to apoptotic cell death induced by DNA damaging agents

HTLV-1 Tax protein sensitizes cells to apoptotic cell death induced by DNA damaging agents

Impact of HTLV-I Tax on cell cycle progression and the cellular DNA damage repair response

Epstein–Barr virus latent membrane protein 1 represses p53-mediated DNA repair and transcriptional activity

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