Tax Increases Frequency of Mutation

There have been several studies that have shown that the expression of Tax in HTLV-1-infected cells increases the frequency of mutations in the cellular genome.86,87 This is presumably mediated by two separate mechanisms, the first of which is dependent on the trans-activation of the proliferating cell nuclear antigen (PCNA).88 PCNA has also been implicated as a necessary factor in both nucleotide excision repair (NER) and mismatch repair (MMR) and also in increasing the processivity of DNA polymerase-delta, an enzyme involved in DNA replication and repair.89,90 DNA-polymerase-delta mediated repair has been shown to play a role in both NER and MMR. PCNA interacts with the cyclin-dependent kinase inhibitor p21 in the presence of DNA damage to block PCNA-dependent DNA replication without dampening PCNA-dependent DNA repair.91,92 Excess

PCNA can overcome this competitive inhibition. The second mechanism is mediated by Tax trans-suppression of DNA-poly-merase-beta.93 DNA-polymerase-beta has been shown to play an important role in base excision repair (BER). Together, these effects would induce the DNA replicative machinery to proceed even in the presence of DNA damage, increasing the frequency of cellular mutations.

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