title: n-Butyrate alters chromatin accessibility to DNA repair enzymes.
abstract: Current evidence suggests that the complex nature of mammalian chromatin can result in the concealment of DNA damage from repair enzymes and their co-factors. Recently it has been proposed that the acetylation of histone proteins in chromatin may provide a surveillance system whereby damaged regions of DNA become exposed due to changes in chromatin accessibility. This hypothesis has been tested by: (i) using n-butyrate to induce hyperacetylation in human adenocarcinoma (HT29) cells; (ii) monitoring the enzymatic accessibility of chromatin in permeabilised cells; (iii) measuring u.v. repair-associated nicking of DNA in intact cells and (iv) determining the effects of n-butyrate on cellular sensitivity to DNA damaging agents. The results indicate that the accessibility of chromatin to Micrococcus luteus u.v. endonuclease is enhanced by greater than 2-fold in n-butyrate-treated cells and that there is a corresponding increase in u.v. repair incision rates in intact cells exposed to the drug. Non-toxic levels of n-butyrate induce a block to G1 phase transit and there is a significant growth delay on removal of the drug. Resistance of HT29 cells to u.v.-radiation and adriamycin is enhanced in n-butyrate-treated cells whereas X-ray sensitivity is increased. Although changes in the responses of cells to DNA damaging agents must be considered in relation to the effects of n-butyrate on growth rate and cell-cycle distribution, the results are not inconsistent with the proposal that increased enzymatic-accessibility/repair is biologically favourable for the resistance of cells to u.v.-radiation damage. Overall the results support the suggested operation of a histone acetylation-based chromatin surveillance system in human cells.
mesh_terms: D002087:Butyrates / Q000494:pharmacology*; D020148:Butyric Acid; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D002843:Chromatin / Q000378:metabolism*; D004260:DNA Repair / Q000187:drug effects*; D003850:Deoxyribonuclease I / Q000378:metabolism; D004317:Doxorubicin; D004706:Endodeoxyribonucleases; D006801:Humans; D009097:Multienzyme Complexes / Q000378:metabolism; D009699:N-Glycosyl Hydrolases; D011740:Pyrimidine Dimers / Q000378:metabolism; D014466:Ultraviolet Rays; D014965:X-Rays
chemical_list: D002087:Butyrates; D002843:Chromatin; D009097:Multienzyme Complexes; D011740:Pyrimidine Dimers; D020148:Butyric Acid; D004317:Doxorubicin; C032219:UV endonuclease; D004706:Endodeoxyribonucleases; D003850:Deoxyribonuclease I; D009699:N-Glycosyl Hydrolases