BLOCKADE OF TELOMERASE FUNCTION BY NUCLEOSIDE ANALOGS

Two types of spontaneously transformed cells appear in the culture of senescent mouse embryonic fibroblasts. The first type are cells with r estricted proliferative potential (up to 30 population doublings); the other type are immortalized cells. Cells of the first type, unlike th ose of the second, have no telomerase activity and undergo two rounds of senescence. Spontaneous transformation of mouse embryonic fibroblas ts in tt ie presence of the reverse transcriptase inhibitors azidothym idine and carbovir led to the formation of telomerase-free clones. A f raction of these clones have tile ability to overcome senescence via t he acquisition of high telomerase activity. Cells with a very high lev el of telomerase activity become resistant to azidothymidine and carbo vir. Azidothymidine-induced artificial senescence of rat myoblasts in culture resembles the senescence of fibroblasts. but the resulting cel ls acquire sharp morphological peculiarities. The blockade of telomera se function by azidothymidine in human U-937 and MeWo cells leads to t he shortening of telomeres, but does not result in senescence. A hypot hesis of the generation of the signal that induces senescence is propo sed. This hypothesis suggests a change iii DNA conformation during tel omere shortening as a result of a change of loop structure of telomeri c chromatin.