Chromatin Regulation of DNA Damage Repair and Genome Integrity in the Central Nervous System

Abstract

With the continued extension of lifespan, aging and age-related diseases have become a major medical challenge to our society. Aging is accompanied by changes in multiple systems. Among these, the aging process in the central nervous system is critically important but very poorly understood. Neurons, as post-mitotic cells, are devoid of replicative associated aging processes, such as senescence and telomere shortening. However, because of the inability to self-replenish, neurons have to withstand challenge from numerous stressors over their lifetime. Many of these stressors can lead to damage of the neurons' DNA. When the accumulation of DNA damage exceeds a neuron's capacity for repair, or when there are deficiencies in DNA repair machinery, genome instability can manifest. The increased mutation load associated with genome instability can lead to neuronal dysfunction and ultimately to neuron degeneration. In this review, we first briefly introduce the sources and types of DNA damage and the relevant repair pathways in the nervous system (summarized in Fig. 1). We then discuss the chromatin regulation of these processes and summarize our understanding of the contribution of genomic instability to neurodegenerative diseases. Abbreviations DDRDNA damage response NHEJnonhomologous end joining HRhomologous recombination BERbase excision repair NERnucleotide excision repair SSBsingle-strand break SSBRsingle-strand break repair DSBRdouble-strand break repair DSBdouble-strand break mtDNAmitochondrial DNA PARpoly(ADP-ribose) HAThistone acetyltransferase HDAChistone deacetylase ATMataxia telangiectasia mutated MMRmismatch repair CNVcopy number variation iPSCinduced pluripotent stem cell HDHuntington's disease ADAlzheimer's disease PDParkinson's disease ALSamyotrophic lateral sclerosis Keywords neurodegenerative diseases DNA repair DNA damage response histone modifications central nervous system