Transglutaminase-mediated crosslinking of specific core histone subunits and cellular senescence.

We observed that the transglutaminase (tTGase) level and activity increased in aged rats and senescent primary fibroblasts, suggesting that the tTGase-mediated macromolecule crosslinking may play a mechanistic role during aging. Although preliminary, our in vitro experiment suggests that the target of tTGase is core histones: H2A:H2B and H3:H4 are specifically crosslinked by tTGase. On the basis of these data, we postulate that the changes of DNA metabolism in association with cellular aging may be ascribed primarily to the crosslinking of core histone subunits. Further speculation awaits substantive data showing increased histone crosslinking in senescent cells and also what crosslinked histones in various DNA metabolisms may imply. At the moment, present data are sufficient to propose that tTGase is a senescence marker and it may be primarily responsible for the phenotypes associated with cellular senescence.