THE EFFECTS OF 5-AZACYTIDINE AND 5-AZADEOXYCYTIDINE ON CHROMOSOME STRUCTURE AND FUNCTION - IMPLICATIONS FOR METHYLATION-ASSOCIATED CELLULARPROCESSES

5-Azacytidine (5-aza-C) analogs demonstrate a remarkable ability to in duce heritable changes in gene and phenotypic expression. These cellul ar processes are associated with the demethylation of specific DNA seq uences. On the other hand, 5-aza-C analogs have dramatic effects on ch romosomes, leading to decondensation of chromatin structure, chromosom al instability and an advance in replication timing. Condensation inhi bition of genetically inactive chromatin occurs when the DNA is still hemimethylated or fully methylated. In cell cultures prolonged for sev eral replication cycles, chromosomal rearrangements and instability af fect the 5-aza-C-sensitive regions. Moreover, the normally late-replic ating inactive chromatin undergoes a transient temporal shift to an ea rlier DNA replication, characteristic of activatable chromatin. zThe i nduced alterations of chromosome structure and behavior may trigger th e 5-aza-C-dependent process of cellular reprogramming. Apart from thei r differentiating and gene-modifying effects, 5-aza-C analogs can tumo rigenically transform cells and modulate their metastatic potential. H igh doses of 5-aza-C analogs have cytotoxic and antineoplastic activit ies.