Interaction of HTLV-1 Tax with minichromosome maintenance proteins accelerates the replication timing program

The Tax oncoprotein encoded by the Human T-cell leukemia virus type 1 (HTLV-1)
plays a pivotal role in viral persistence and pathogenesis. HTLV-1 infected cells proliferate
faster than normal lymphocytes, expand through mitotic division and accumulate genomic
lesions. Here, we show that Tax associates with the minichromosome maintenance MCM2-7
helicase complex and localizes to origins of replication. Tax modulates the spatiotemporal
program of origin activation and fires supplementary origins at the onset of S phase. Thereby,
Tax increases the DNA replication rate, accelerates S phase progression but also generates a
replicative stress characterized by the presence of genomic lesions. Mechanistically, Tax
favors p300 recruitment and histone hyperacetylation at late replication domains advancing
their replication timing in early S phase.