n-Butyrate alters chromatin accessibility to DNA repair enzymes.
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.
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
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