DNA repair deficiency and neurological disease

Abstract

PrefaceResponding to genotoxic stress is a prerequisite for development of the nervous system. Mutations in a variety of DNA repair factors can lead to human diseases that are characterized by pronounced neuropathology. In many of these syndromes the neurological component is amongst the most deleterious aspects of the disease. The nervous system poses a particular challenge in terms of clinical intervention, as the neuropathology often arises during nervous system development, and can be fully penetrant by childhood. Understanding how DNA repair deficiency impacts the nervous system will provide a rationale basis for therapies targeted at ameliorating the neurological problems in these syndromes. [1] IntroductionMaintaining genomic integrity by DNA repair is fundamental to the function and survival of an organism. Compromising genomic DNA can lead to a spectrum of human disorders that exhibit developmental defects, immune deficiency and cancer. In particular, the nervous system is often profoundly affected by DNA repair deficiency, which can result in neurodegeneration, microcephaly or brain tumors. More broadly, defective DNA repair in mature neural tissues has also been linked to aging and recently to common neurodegenerative syndromes such as Alzheimer's disease and Parkinson disease [1][2][3][4] .The developmental dynamics of the nervous system requires vigilant DNA repair processes capable of repairing multiple types of damage. DNA repair is especially critical during the early period of rapid proliferation as progenitors expand and differentiate to generate the nervous system. In the mature nervous system, DNA repair is also essential to prevent DNA damage, arising from sources such as oxidative metabolism, from blocking active transcription. Understanding the interplay between signaling networks that function to maintain genomic stability in the nervous system will be of paramount importance for the Resources NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript treatment of diseases associated with DNA repair deficiency. This review will discuss the role of DNA repair during the genesis of the nervous system, and how this process maintains neural homeostasis.[2] The importance of DNA integrity during neural developmentMany human DNA repair syndromes are congenital and so it is clear that the developing nervous system can be markedly affected by DNA repair deficiency. Therefore, understanding neural development is important for determining how DNA repair deficiency impacts the nervous system. Detailed reviews that summarize neural development are available [5][6][7][8][9] . In humans, the nervous system begins to form during the first trimester of gestation and continues until after birth. The complexity of the mature nervous system results from a relatively simple strategy of proliferation, differentiation and migration (Fig. 1). The engine driving neural development is rapid cellular proliferation within the ventricular and subventricular zones that line the four ventricles presen...

DNA-PK promotes the survival of young neurons in the embryonic mouse retina

“…The accumulation of DSBs may be the result of DNA replication, transcription or oxidative metabolism, as postulated to explain the impact of deficient DSB repair in development. 11,12,32 However, these alternatives do not explain the selectivity of the tissues and cells affected, the immune and nervous systems 2,6 and, more specifically, the effects on young neurons in both knockout animals and through our pharmacological approach. 5,7,8,11 One might speculate that in the central nervous system, as in the immune system, DSBs underlie genomic rearrangements that trigger apoptosis if not adequately repaired.…”

“…Although NHEJ is an error-prone repair process, it is considered to be the predominant pathway in mammals. 7,12 DSBs trigger a signaling cascade that leads to the rapid formation of a repair focus at the break. One of the earliest events in DNA damage response is the Ser139 phosphorylation of histone H2AX (gH2AX) by members of the phosphatidylinositol-3 kinase-like family, such as ataxia telangiectasia and Rad-3 related (ATR), ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PK).…”

“…During normal embryonic development, DSBs are likely to be a consequence of endogenous cellular activity and may be caused by replication stress during proliferation, transcriptional activity or oxidative stress produced by normal metabolism. 11,12 In addition, DSBs can be programmed to generate diversity in the immune system. 13 In eukaryotes, DSBs are repaired by either homologous recombination (HR) or nonhomologous end-joining (NHEJ).…”

“…Although these kinases share downstream substrates and cooperate under certain conditions, they have nonredundant functions. 12,14,15 Both ATR and ATM are checkpoint kinases that coordinate cell cycle progression after DNA damage. Whereas ATR is activated by singlestranded overhangs generated at DSBs or single-stranded DNA originated from stalled replication forks during the S phase, ATM responds to DSBs 15,16 and it has been implicated in the NHEJ repair pathway.…”

Double-strand break repair by homologous recombination in primary mouse somatic cells requires BRCA1 but not the ATM kinase

“…We also investigated HDR levels in primary cells from other tissues. In the nervous system, both HDR and NHEJ defects have been associated with developmental abnormalities and tumorigenesis (20). To assess HDR levels in the developing brain, primary cultures were derived from neonatal brains, which primarily consist of cells of glial origin (21).…”