Telomere attrition induces a DNA double-strand break damage signal that reactivates p53 transcription in HTLV-I leukemic cells

Datta, Abhik; Nicot, Christophe

doi:10.1038/sj.onc.1210718

Cited by 17 publications

(13 citation statements)

References 29 publications

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“…Dysfunctional telomeres are strongly linked to the activation of the ATM-p53 DNA damage response. 30 Phosphorylation of p53 on serine 20 and specific localization were readily detected in late passage Tax-transduced PBMCs ( Figure 2H). Expression of p53-responsive genes, p21waf and mdm2, was also increased ( Figure 2I).…”

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confidence: 99%

HTLV-I Tax-dependent and -independent events associated with immortalization of human primary T lymphocytes

Bellon

Baydoun

Yao

et al. 2010

Blood

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Human T-cell leukemia virus type I (HTLV-I IntroductionHuman T-cell leukemia virus type I (HTLV-I) transforms human CD4 ϩ T cells in vitro and in vivo causing adult T-cell leukemia/ lymphoma (ATL). 1 ATL has an extremely poor prognosis for survival, characterized by an aggressive proliferation of leukemic cells. 2 The molecular basis for HTLV-I-mediated transformation of T cells is unclear. Tax has been shown to inactivate several tumor suppressors, disrupt cell cycle and DNA repair checkpoints, and stimulate cell growth, while protecting against apoptosis. [3][4][5][6][7] Importantly, the oncogenic activities of Tax have been studied mainly in transgenic models and in rodent fibroblasts. [8][9][10] Although these models provided useful information, they have limitations, because the transformation of human cells in vitro requires more oncogenic events than the transformation of rodent cells. 11 The role of Tax in transformation is based largely on forced overexpression of Tax, which results in cell-cycle abnormalities, faulty mitosis, aneuploidy, and the formation of multinucleated cells. A major caveat to these studies is that they were performed in established cell-culture lines, which are already dysfunctional in key regulatory pathways (tumor suppressor, cell cycle, and DNA repair checkpoints), and therefore are much more susceptible than normal primary cells to Tax-induced alterations. Studying Tax in human primary T cells is preferable, yet, to date, immortalized Tax-expressing human T-cell lines able to proliferate indefinitely in culture have not been established. In one study, the pX region of HTLV-I (which expresses the Tax gene among other viral genes) was found to transform human T cells in the context of a Herpesvirus saimiri vector, 12 although there is no evidence to refute that the herpes genes from the vector synergized or were activated by Tax to promote transformation or that other viral genes were involved. This prompted us to investigate the ability of Tax to immortalize human primary T cells. In the following study, we demonstrate that Tax-induced immortalization of peripheral blood mononuclear cells (PBMCs) is a very rare event. Tax alone enhanced proliferation, but appears insufficient to sustain permanent proliferation. Although most attempts were unsuccessful, we finally obtained an immortalized Tax-expressing CD4 human T-cell line, WT4, which was maintained in continuous culture for more than 4 years. Our results suggest that Tax alone is a poor oncogene that increases the life span and rate of T-cell proliferation in the presence of interleukin-2 (IL-2), thereby increasing the probability for accumulation of genetic defects leading to immortalization. Methods Plasmids and cell linesThe HTLV-I tax gene was cloned into the HRCMV or HRЈ lentiviral vectors ( Figure 1A). Pseudotype virus particles were produced as previously reported. 13 For cell-cycle analysis, tax was cloned into an UBC-IRES-GFP lentiviral vector. The p53 gene of WT4 was sequenced and cloned as previously described. 14 ...

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confidence: 99%

HTLV-I Tax-dependent and -independent events associated with immortalization of human primary T lymphocytes

Bellon

Baydoun

Yao

et al. 2010

Blood

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“…[18][19][20] Recently, Tax has been proposed to induce constitutive signaling of the DNA-PK pathway 21 and to attenuate the ATM-mediated cellular DNA-damage response, 22 and ATM has been shown to be hyperphosphorylated in HTLV-1-transformed cells. 23 However, a role for other HTLV-1 viral proteins in genomic stability has been overlooked. In the present study, we report for the first time that HTLV-1 p30 is specifically redistributed from the nucleolus to the nucleoplasm upon DNA damage.…”

Section: Introductionmentioning

confidence: 99%

Human T-lymphotropic type 1 virus p30 inhibits homologous recombination and favors unfaithful DNA repair

Baydoun

Pancewicz

Nicot

2011

Blood

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IntroductionHomologous recombination (HR) is a major pathway of doublestrand break (DSB) repair in mammalian cells. 1 Faithful recombination is critical to avoid genetic and genomic aberrations, and involves a complex and orderly assembly of many checkpoints and repair factors. DSBs frequently occur as a result of exposure to irradiation and chemicals. In response to DSBs, activation of ataxia telangiectasia mutated (ATM) initiates a cascade of events, including phosphorylation of histone H2AX (referred to as ␥-H2AX) and downstream effectors such as structural chromosome maintenance 1 (SCM1) and checkpoint kinase 2 (Chk2). 2,3 Chk2 phosphorylates p53, disrupting its interaction with Mdm2 and stabilizing the p53 protein, 4 which pauses the cell cycle so that the cell can attempt to repair its damaged DNA. H2AX phosphorylation plays an important role in both DNA-damage-checkpoint activation and deactivation of the checkpoint signal to allow the cell cycle to resume. HR is very important during DNA replication in the S phase, when DSBs are generated during lagging strand synthesis or when unrepaired lesions cause replication-fork stalling. 5,6 Initiation of HR involves the recruitment of the MRE11/RAD50/NBS1 (MRN) complex to DNA-damaged sites that can be visualized by accumulation of ␥-H2AX as foci. 7 In contrast, DSBs created during the G1 or M phase are preferentially repaired by a nonconservative, nonhomologous-endjoining (NHEJ) pathway. The NHEJ pathway has been shown to be Ku80 and DNA-dependent protein kinase (DNA-PK) dependent. 8 The switch from HR to NHEJ has not been fully elucidated, but can in part be explained by the fact that MRE11-resection activity generates single-stranded DNA for which Ku80 has a poor affinity, allowing for the assembly of the MRN complex and HR repair. Therefore, regulation of DSB access to MRE11 or Ku80 is likely decisive in the fate and type of DNA repair.HTLV-1 is a human retrovirus associated with adult T-cell leukemia/lymphoma, an aggressive disease with a dismal prognosis. 9 Whereas the majority of HTLV-1-infected individuals remain asymptomatic, upwards of 5% of patients ultimately develop adult T-cell leukemia/lymphoma. The molecular mechanisms of HTLV-1 oncogenesis are poorly understood. HTLV-1 disrupts cell-cycle checkpoints, tumor suppressors, and Notch signaling and reactivates telomerase. [10][11][12][13] Unlike animal oncoretroviruses, HTLV-1 does not transduce a protooncogene and does not integrate at specific sites in the human genome, thereby excluding insertional mutagenesis. The end of the HTLV-1 proviral genome encodes for the regulatory proteins p12, p30, and the HTLV-1 bZIP factor (HBZ), which are involved in virus infectivity, immune escape, and establishment of latency. 14-17 HTLV-1 leukemic cells often present numerous genomic alterations, but the genesis and contribution of these chromosomal defects are presently unclear. The viral oncoprotein Tax plays an important role in the initiation of cellular transformation. In addition, several studies have shown...

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“…Perhaps the most-studied anti-retroviral drug is zidovudine (AZT), which is used extensively to treat HIV-1-infected individuals. Despite early reports suggesting that zidovudine provided some level of anticancer effect in ATL patients [170,171], ATL cells do not appear to exhibit a high degree of apoptosis in response to zidovudine, even in combination with IFNα [172], and the mechanism of inhibition is likely through telomere attrition and reactivation of a p53-dependent senescent pathway [79,173,174].…”

Section: Treatment Of Htlv-1: Drug-induced Apoptosismentioning

confidence: 93%

“…Tax-mediated inactivation of p53 is believed to occur through p53 phosphorylation on specific residues [74,78]. As well, a recent study also suggests that the transcriptional repressor of p53, MdmX, is up-regulated in HTLV-I infected cells in vitro and in vivo, and may play an important role in the inactivation of p53 in the absence of Tax expression [79]. The ability of Tax to repress the nontranscriptional functions of p53 is intriguing.…”

Section: Htlv-i Tax: Regulation Of Nf-κb Akt and Gene Expressionmentioning

confidence: 99%

HTLV-1 and apoptosis: role in cellular transformation and recent advances in therapeutic approaches

Taylor

Nicot

2008

Apoptosis

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A universal cellular defense mechanism against viral invasion is the elimination of infected cells through apoptotic cell death. To counteract host defenses many viruses have evolved complex apoptosis evasion strategies. The oncogenic human retrovirus HTLV-I is the etiological agent of adult-T-cell leukemia/lymphoma (ATLL) and the neurodegenerative disease known as HTLVassociated myelopathy/tropical spastic paraparesis (HAM/TSP). The poor prognosis in HTLV-Iinduced ATLL is linked to the resistance of neoplastic T cells against conventional therapies and the immunocompromised state of patients. Nevertheless, several studies have shown that the apoptotic pathway is largely intact and can be reactivated in ATLL tumor cells to induce specific killing. A better understanding of the molecular mechanisms employed by HTLV-I to counteract cellular death pathways remains an important challenge for future therapies and the treatment of HTLV-Iassociated diseases.

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Telomere attrition induces a DNA double-strand break damage signal that reactivates p53 transcription in HTLV-I leukemic cells

Cited by 17 publications

References 29 publications

HTLV-I Tax-dependent and -independent events associated with immortalization of human primary T lymphocytes

HTLV-I Tax-dependent and -independent events associated with immortalization of human primary T lymphocytes

Human T-lymphotropic type 1 virus p30 inhibits homologous recombination and favors unfaithful DNA repair

HTLV-1 and apoptosis: role in cellular transformation and recent advances in therapeutic approaches

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