DNA strand break repair and neurodegeneration
Introduction
The genome is constantly under attack from endogenous and exogenous genotoxic agents, and also possesses an inherent level of instability [1]. Breaks can arise in one or both DNA strands, and chemical adducts or crosslinks can arise on or between DNA bases [2], [3], [4]. In addition, the breakage and repair of cellular DNA is also a necessary part of several cellular processes critical for cellular growth and proliferation and for organismal development. Genome stability and maintenance requires a number of overlapping biochemical pathways involving many different proteins, clustered into specific DNA repair pathways. Loss of function of these proteins can lead to a variety of disorders, with pathologies including growth and developmental defects, immunodeficiency, cancer, neurodegeneration and ageing [5], [6], [7]. The association of DNA repair defects with both elevated predisposition to cancer and to increased rates of neurodegeneration and ageing, sometimes in the same genetic disease, is particularly intriguing, because cancer is a disease of excessive cell growth and survival, whereas neurodegeneration is a disease of excessive cell dysfunction and death. Opposite cellular end points can thus arise from defects in common or related processes [8]. In this review we focus on DNA damage defective diseases associated with neurological dysfunction, and attempt to rationalise the differences in underlying molecular defects between developmental and neurodegenerative pathologies.
Section snippets
Brain development
Embryonic development involves waves of rapid cell division throughout the developing embryo, followed by complex periods of migration and differentiation (Fig. 1) [9]. During this time there is a requirement for rapid and efficient mechanisms to fix transcription- and replication-associated DNA breaks as well as naturally occurring oxidative breaks. Failure to repair these breaks may lead to the accumulation of damage and cell death, resulting in neuronal loss at different stages of
Double strand break repair and neurogenesis
Double strand break repair (DSBR) involves two distinct pathways (Fig. 2) [16]: during G1 and early S-phase, the dominant repair pathway involves the processing and ligation of non-homologous DNA ends (non-homologous end joining; NHEJ). The principal components of NHEJ are DNA-dependent protein kinase (DNA-PK), XRCC4, DNA ligase 4 (Lig4) and XLF/Cernunnos. Damaged DNA termini are processed primarily by PNKP, TDP2, Artemis, aprataxin, or by one of several nucleases, which prepare the DNA ends
Progressive neurodegeneration and cerebellar ataxia
Whilst DSBs are severe lesions that impact greatly on proliferating and differentiating cells, and consequently on neurodevelopment, these lesions are relatively rare. In contrast, lesions on a single strand of DNA, and in particular single-strand breaks (SSBs), arise 3 orders of magnitude more frequently. Single-strand lesions are normally repaired rapidly by the SSBR and TC-NER pathways (Fig. 4), but if these pathways are defective, long-lived single-strand lesions can trigger cell death by
Conclusion
Recent data from transgenic models has enabled us to resolve the overlapping neurological phenotypes in DNA repair disorders. As illustrated in Fig. 1, these disorders can be categorised into early developmental (embryonic lethality) mid-to-late developmental (microcephaly) or post-developmental (neurodegenerative). Broadly-speaking, these categories are defined by the repair pathway that is defective, with a requirement for HR particularly evident during early development, NHEJ during late
Conflict of interest statement
None.
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