POLY (ADP-RIBOSYL)ATION OF VARIANT HISTONES AND POSSIBLE IMPLICATIONS IN CARCINOGENESIS

Abstract

Poly(ADP-ribose) is a third species of nucleic acids. The rapid synthesis and degradation of poly(ADP-ribose) is a dynamic nuclear process that seems to be involved in carcinogenesis via its implication in repair, replication, gene expression, recombination and chromatin remodeling in development. In the present study, the ADP-ribosylated species of histones synthesized in human erythroid K562 cell nuclei were examined by high-resolution two-dimensional polyacrylamide gel electrophoresis. Modification of core histone variants appears to be highly specific. Variants of histone H3 are modified with one or more than five ADP-ribosyl groups, whereas the concentrations of di-, tri- and tetra(ADP-ribosyl)ated H3 is extremely low. This is in contrast to the presence of a continuous ladder of mono- to poly(ADP-ribosyl)ated species for the variants of H2B, H2A, H1 and H4. The order of poly(ADP-ribosyl)ation of core histones in isolated nuclei is H2B > H2A.X > H3.2,3 approximately H4 > H2A.Z approximately H3. 1. A model is proposed to explain how mono- and oligo(ADP-ribosyl)ated core histones containing 1 - 7 ADP-ribosyl groups might unfold higher-order chromatin structures and open individual nucleosomes into transcriptionally poised structures. The relevance of these studies to molecular carcinogenesis are discussed.