Title:The Genetic and Epigenetic Effects of 5-Azacytidine and its Major Breakdown Product Guanylurea
VOLUME: 1 ISSUE: 1
Author(s):Katarzyna Lamparska and Steven S. Smith
Affiliation:Beckman Research Institute and the Division of Urology, Familian Science Building, City of Hope, 1500 E. Duarte Roadd, Duarte CA 91010, USA.
Keywords:Azacytidine, double strand break repair, fragile sites, guanylurea, methytransferase, structure specific nuclease.
Abstract:It is now possible to describe the known genetic and epigenetic effects of 5-
azacytidine in terms of its ability and the ability of its primary breakdown product
(guanylurea) to produce replication stress, through their combined effects in
sequestering DNA methyltransferases and hindering DNA replication. Sequestration
of methyltransferases can account for most of the epigenetic changes seen in surviving
cells (e.g. hypomethylation), while the resulting replication stress produces all the
expected genetic changes associated with this 5-azacytidine exposure (e.g.
mutagenesis, induction of double strand breaks, induction of fragile sites, and
induction of sister chromatid exchange at fragile sites) in addition to contributing to hypomethylation. Nearly all of these
effects have now been documented in different disciplines. Collectively, they form a more complete picture of the direct
and indirect effects of the action of 5-azacytidine and its breakdown products that link structure specific nucleases like
ERCC1and MUS81-EME to the genetic damage that these drugs produce, and suggests that double strand break repair
and the B and non-B DNA structures it produces play important roles in 5-azacytidine induced gene activation.
