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

Mechanisms of HTLV-1 persistence and transformation

“…This pathway is orchestrated by ATM, ATR and DNA-PK kinases whose substrates (e.g., CHK1, -2, p53, H2AX, 53BP1) delay cell cycle progression, promote DNA repair or even elicit permanent proliferative arrest (i.e., senescence) and apoptosis in case of extended, irreparable, DNA lesions. De novo TAX expression causes checkpoint activation and cell cycle arrest in G1 and G2/M phases of the cell cycle, consistent with the fact that TAX triggers genome instability (Marriott and Semmes, 2005). Our unpublished data indicate that TAX-dependent acceleration of the cell cycle induces replicative DNA damage resulting in constitutive DDR pathway activation in TAX-transformed cells as well as in T lymphocytes isolated from ATL patients (Boxus M and Willems L, unpublished data).…”

“…Although only a small percentage of ATL patients have genomic p53 mutations, the TAX protein interferes with the DDR pathway through inactivation of p53 (for a review see (Tabakin-Fix et al, 2006)). TAX also restricts activity of ATM, DNA -PK, CHK1 and CHK2-mediated checkpoints at G1 or G2/M (Marriott and Semmes, 2005;Chandhasin et al, 2008;Durkin et al, 2008). As a result, TAX limits cell cycle arrest induced by exogenous DNAdamaging agents.…”

“…A major activity of TAX is stimulation of G1/S transition (Marriott and Semmes, 2005). Mechanistically, TAX increases the levels of type D cyclins in G1 and activates cyclindependent kinases (i.e., CDK4 and CDK6) through direct binding, leading to hyperphosphorylation of Rb, subsequent release of E2F transcription factor and accelerated transition from G1 to S. TAX also directly interacts with and promotes proteasomal degradation of Rb.…”

“…On one hand, TAX represses expression of DNA polymerase-b that is involved in base excision repair and inhibits nucleotide excision repair induced by UV irradiation (Marriott and Semmes, 2005). On the other hand, TAX represses expression of the human telomerase reverse transcriptase (hTERT) and subverts Ku80 activity, thereby reducing protection from double-strand breaks (DSB) as well as telomere extension (Matsuoka and Jeang, 2007).…”

Retracted: Overexpression of Aurora A by loss of CHFR gene expression increases the growth and survival of HTLV‐1‐infected T cells through enhanced NF‐κB activity

“…21 Tax activates NF-jB pathways by physically targeting IKK complexes. 19 In addition to dysregulation of cellular NF-jB signaling pathways, HTLV-1-infected T-cell lines and ATL cells show dysregulation of mitotic checkpoint proteins, 22,23 and HTLV-1 Tax is known to affect centrosome numbers. 24 Aurora A is involved in centrosome duplication, and abnormal centrosomal duplication is important for retroviral pathogenesis.…”