Higher order chromatin degradation: implications for neurodegeneration

Higher order chromatin degradation (HOCD) is a hallmark of programmed cell death. HOCD is mediated by enzymatic digestion of the DNA backbone at matrix attachment regions, and ultimately results in the excision of chromatin loops and their oligomers from chromosomes. We have recently demonstrated that hydrogen peroxide (H₂O₂), the major mediator of oxidative stress, rapidly induces HOCD. This demonstration allowed us to characterize several kinetic features of HOCD. Moreover, H₂O₂-induced HOCD provides a mechanistic link between oxidative stress and the pathology of neurodegeneration. Thus, in acute neurodegenerative conditions, which feature severe oxidative stress, H₂O₂-induced HOCD efficiently dismantles the genome, and thus, irreversibly commits cells to death. In chronic neurodegenerative conditions, which feature sublethal but perennial oxidative stress, cells undergo only a partial fragmentation of the genome via H₂O₂-induced HOCD. If unrepaired of improperly repaired, such a partial fragmentation leads to the generation and accumulation of somatic mutations that are likely to play the key role in delayed degeneration and death of neural cells.