HTLV-I Tax-Mediated Inactivation of Cell Cycle Checkpoints and DNA Repair Pathways Contribute to Cellular Transformation: “A Random Mutagenesis Model”

Abstract

To achieve cellular transformation, most oncogenic retroviruses use transduction by proto-oncogene capture or insertional mutagenesis, whereby provirus integration disrupts expression of tumor suppressors or proto-oncogenes. In contrast, the Human T-cell leukemia virus type 1 (HTLV-I) has been classified in a separate class referred to as “transactivating retroviruses”. Current views suggest that the viral encoded Tax protein transactivates expression of cellular genes leading to deregulated growth and transformation. However, if Tax-mediated transactivation was indeed sufficient for cellular transformation, a fairly high frequency of infected cells would eventually become transformed. In contrast, the frequency of transformation by HTLV-I is very low, likely less than 5%. This review will discuss the current understanding and recent discoveries highlighting critical functions of Tax in cellular transformation. HTLV-I Tax carries out essential functions in order to override cell cycle checkpoints and deregulate cellular division. In addition, Tax expression is associated with increased DNA damage and genome instability. Since Tax can inhibit multiple DNA repair pathways and stimulate unfaithful DNA repair or bypass checkpoints, these processes allow accumulation of genetic mutations in the host genome. Given this, a “Random Mutagenesis” transformation model seems more suitable to characterize the oncogenic activities of HTLV-I.

Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1–infected T cells

“…79 Given the constant expression of HBZ in all HTLV-1-infected cells, these data may provide a clue to explain the underlying mechanisms of p53 inactivation in ATL cells in the absence of Tax expression in majority of cases. 22 The Rb tumor suppressor gene is infrequently altered in structure 77,80 ; however, ;50% of ATL cases exhibit loss of Rb protein. 81 Additionally, low levels of Rb expression correlated with poor prognosis and shorter survival.…”

“…Therefore, Tax is considered to be a main viral factor involved in immortalization and transformation of the infected cells. [18][19][20][21][22] HTLV-1 also expresses a minus-strand RNA that can encode a basic leucine zipper factor, HTLV-1 bZIP factor (HBZ). 23,24 HBZ messenger RNA (mRNA) was shown to promote the proliferation of ATL cells.…”

The Human T-Cell Leukemia Virus Type 1 Basic Leucine Zipper Factor Attenuates Repair of Double-Stranded DNA Breaks via Nonhomologous End Joining

“…Given that the viral protein Tax is known to have substantial effects on DSB repair (117,118), it was important to understand how HBZ and Tax, together, affect the repair process. Interestingly, Tax has been shown to saturate the NHEJ repair pathway through two distinct mechanisms.…”

Undifferentiated Pleomorphic Sarcoma and the Importance of Considering the Oncogenic and Immune-Suppressant Role of the Human T-Cell Lymphotropic Virus Type 1: A Case Report

“…In this context, Johnson et al reported that Tax affects cell-cycle regulatory molecules, stabilizes, and inactivates the tumor suppressor p53 in HTLV-1 transformed cell lines by inducing hyperphosphorylation of p53 (19). Considering the “Random Mutagenesis transformation model” proposed to characterize the oncogenic activities of HTLV-1 (2), we could hypothesize that mutations linked to the UPS could have likely been produced in this case. Further research on gene–gene and gene–environment interactions of this oncogenic virus is need.…”

“…Tax can inhibit multiple DNA repair pathways and stimulate incorrect DNA repair allowing accumulation of genetic mutations in the host genome and contributing to cellular transformation. This mechanism has recently been named by Nicot et al as “Random Mutagenesis Model” to characterize one of the oncogenic features of HTLV-1 (2). …”