HUMAN FIBROBLAST COMMITMENT TO A SENESCENCE-LIKE STATE IN RESPONSE TOHISTONE DEACETYLASE INHIBITORS IS CELL-CYCLE DEPENDENT

Human diploid fibroblasts (HDF) complete a limited number of cell divi sions before entering a growth arrest state that is termed replicative senescence. Two histone deacetylase inhibitors, sodium butyrate and t richostatin A, dramatically reduce the HDF proliferative life span in a manner that is dependent on one or more cell doublings in the presen ce of these agents. Cells arrested and subsequently released from hist one deacetylase inhibitors display markers of senescence and exhibit a persistent G(1) block but remain competent to initiate a round of DNA synthesis in response to simian virus 40 T antigen. Average telomere length in prematurely arrested cells is greater than in senescent cell s, reflecting a lower number of population doublings completed by the former. Taken together, these results support the view that one compon ent of HDF senescence mimics a cell cycle-dependent drift in different iation state and that propagation of HDF in histone deacetylase inhibi tors accentuates this component.