γH2Ax: Biomarker of Damage or Functional Participant in DNA Repair All that Glitters Is not Gold!

The phosphorylation of H2Ax on its S139 site, gamma H2Ax, is important for the assembly of repair complexes at DNA double strand breaks (DSBs). The formation and functional role of gamma H2Ax after other kinds of DNA damage, especially UV light, where DSBs are rare, is less clear. Following UV light in the UVB and UVC ranges, complex distributions of gamma H2Ax can be identified, quite unlike the discrete enumerable foci seen after ionizing radiation. Several distinct distributions of gamma H2Ax occur: a low level nuclear-wide distribution of gamma H2Ax occurs during nucleotide excision repair; irregular focal distributions occur at arrested replication forks; high intensity nuclear-wide gamma H2Ax occurs in association with S-phase apoptosis. The intensity and distributions of gamma H2Ax vary according to the activity of excision repair, bypass polymerase and apoptotic caspases. The frequency of DSBs at arrested replication forks is low but highly variable in different cell types, and probably caused by enzymatic action. Despite the prominence of S139 phosphorylation following UV damage, mutation of this site has no influence on the UV damage response indicating that gamma H2Ax is a biomarker but not a participant in the UV-DNA damage response.