Inhibition of histone deacetylase in cancer cells slows down replication forks, activates dormant origins, and induces DNA damage.

ABSTRACT: Protein acetylation is a reversible process regulated by histone deacetylases (HDAC) that is often altered in human cancers. Suberoylanilide hydroxamic acid (SAHA) is the first HDAC inhibitor to be approved for clinical use as an anticancer agent. Given that histone acetylation is a key determinant of chromatin structure, we investigated how SAHA may affect DNA replication and integrity to gain deeper insights into the basis for its anticancer activity. Nuclear replication factories were visualized with confocal immunofluorescence microscopy and single-replicon analyses were conducted by genome-wide molecular combing after pulse labeling with two thymidine analogues. We found that pharmacologic concentrations of SAHA induce replication-mediated DNA damage with activation of histone gammaH2

SUBMITTER: Conti C 

PROVIDER: S-EPMC2880188 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature