Class I histone deacetylase inhibitors inhibit the retention of BRCA1 and 53BP1 at the site of DNA damage.
Bottom Line: Reflecting their effects on histone modifications, the HDAC inhibitors inhibit ionizing radiation-induced foci (IRIF) formation of BRCA1 and BARD1 as well as 53BP1 and RIF1, whereas UNC0638 suppresses IRIF formation of BRCA1 and BARD1 but not 53BP1 and RIF1.Although HDAC inhibitors suppressed HDR, they did not cooperate with the poly(ADP-ribose) polymerase inhibitor olaparib to block cancer cell growth, possibly due to simultaneous suppression of NHEJ pathway components.Collectively, these results suggest the mechanism by that HDAC inhibitors inhibit both the HDR and NHEJ pathways, whereas HKMT inhibitor inhibits only the HDR pathway; this finding may affect the chemosensitizing effects of the inhibitors.
Affiliation: Department of Translational Oncology, St. Marianna University Graduate School of Medicine, Kawasaki, Japan.Show MeSH
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Mentions: To evaluate the effects of HDAC inhibitors and UNC0638 on HDR, we used the gene conversion assay with DR-GFP reporter cells. Treatment with HDAC inhibitors reduced HDR at I-SceI nuclease-induced DSB (Fig.5a,b). The percentages of homologous recombination in cells treated with MS-275 and FK228 relative to that in cells treated with DMSO were 53.7% and 68.8%, respectively (Fig.5b). The effect was modest when compared to UNC0638, which reduced HDR to 38.9% (Fig.5a,b). We also analyzed the IRIF composed of RAD51, the effector of HDR. MS-275, FK228 and UNC0638 all reduced the formation of IRIF of RAD51, although the effect of FK228 was modest at the doses tested. The RAD51-IRIF-positive fractions in cells treated with DMSO, MS-275, FK228 and UNC0638 were 71.4%, 20.7%, 47.0% and 30.6%, respectively (Fig.5c).
Affiliation: Department of Translational Oncology, St. Marianna University Graduate School of Medicine, Kawasaki, Japan.