NF-κB-Induced R-Loops and Genomic Instability in HTLV-1-Infected and Adult T-Cell Leukemia Cells.

Human T-cell leukemia virus type 1 (HTLV-1) is a human delta retrovirus that causes adult T-cell leukemia/lymphoma (ATL) in 3-5% of the infected population after decades of clinical latency. HTLV-1 Tax is a potent activator of IKK/NF-κB and a clastogen. While NF-κB activities are associated with cell survival and proliferation, constitutive NF-κB activation (NF-κB hyperactivation) by Tax leads to senescence and oncogenesis.

NF-κB-induced R-loop accumulation and DNA damage select for nucleotide excision repair deficiencies in adult T cell leukemia.

Constitutive NF-κB activation (NF-κB) confers survival and proliferation advantages to cancer cells and frequently occurs in T/B cell malignancies including adult T cell leukemia (ATL) caused by human T-cell leukemia virus type 1 (HTLV-1). Counterintuitively, NF-κB by the HTLV-1 transactivator/oncoprotein Tax induces a senescence response, and HTLV-1 infections in culture mostly result in senescence or cell-cycle arrest due to NF-κB How NF-κB induces senescence, and how ATL cells maintain NF-κB and avert senescence, remain unclear. Here we report that NF-κB by Tax increases R-loop accumulation and DNA double-strand breaks, leading to senescence.

HTLV-1 Replication and Adult T Cell Leukemia Development.

Human T-cell leukemia virus type 1 (HTLV-1) was discovered in 1980 as the first, and to date, the only retrovirus that causes human cancer. While HTLV-1 infection is generally asymptomatic, 3-5% of infected individuals develop a T cell neoplasm known as adult T cell leukemia/lymphoma (ATL) decades after infection. Since its discovery, HTLV-1 has served as a model for understanding retroviral oncogenesis, transcriptional regulation, cellular signal transduction, and cell-associated viral infection and spread.

RNF8 Dysregulation and Down-regulation During HTLV-1 Infection Promote Genomic Instability in Adult T-Cell Leukemia.

The genomic instability associated with adult T cell leukemia/lymphoma (ATL) is causally linked to Tax, the HTLV-1 viral oncoprotein, but the underlying mechanism is not fully understood. We have previously shown that Tax hijacks and aberrantly activates ring finger protein 8 (RNF8) - a lysine 63 (K63)-specific ubiquitin E3 ligase critical for DNA double-strand break (DSB) repair signaling - to assemble K63-linked polyubiquitin chains (K63-pUbs) in the cytosol. Tax and the cytosolic K63-pUbs, in turn, initiate additional recruitment of linear ubiquitin assembly complex (LUBAC) to produce hybrid K63-M1 pUbs, which trigger a kinase cascade that leads to canonical IKK:NF-κB activation.

Cells of adult T-cell leukemia evade HTLV-1 Tax/NF-κB hyperactivation-induced senescence.

Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma (ATL). The HTLV-1 viral -activator/oncoprotein Tax is a major driver of ATL, yet it induces rapid p21 (p21)- and p27-mediated cellular senescence through constitutive activation (hyperactivation) of NF-κB. Although constitutive NF-κB activation is a common feature of T/B-cell leukemia/lymphoma, including ATL, it is not known how ATL cells maintain chronic NF-κB activation without undergoing senescence.