Maintaining genome stability in the nervous system

Abstract

Active maintenance of genome stability is a prerequisite for the development and function of the nervous system. The high replication index during neurogenesis and the long life of mature neurons highlight the need for efficient cellular programs to safeguard genetic fidelity. Multiple DNA damage response pathways ensure that replication stress and other types of DNA lesions, such as oxidative damage, do not affect neural homeostasis. Numerous human neurologic syndromes result from defective DNA damage signaling and compromised genome integrity. These syndromes can involve different neuropathology, which highlights the diverse maintenance roles that are required for genome stability in the nervous system. Understanding how DNA damage signaling pathways promote neural development and preserve homeostasis is essential for understanding fundamental brain function.

Figure 1. Different DNA repair pathways function during neural development

Neural development encompasses widespread proliferation, migration and differentiation to generate neurons and glia of the adult nervous system. At different stages of development the nervous system is susceptible to different types of DNA damage. During proliferation, replication associated DNA strand breaks can occur that may require DNA double strand break repair (DSBR), involving homologous recombination (HR) or non-homologous end joining (NHEJ). Mismatch repair (MMR) is also important during replication. HR is dependent on replicated sister chromatids for use as an error-free repair template, and so this pathway is not available in non-replicating or differentiated cells. In non-cycling cells, NHEJ repairs DNA double strand breaks while other types of DNA damage require the single strand break repair (SSBR) pathway or nucleotide excision repair (NER). An alternate outcome to DNA damage in replicating and immature, non-differentiated neural cells is apoptosis, while DNA lesions in differentiated cells do not activate apoptosis but instead can interfere with transcription.

Figure 2. DNA damage signaling in the nervous sytem involves ATM and ATR

ATM (ataxia telangiectasia, mutated) and ATR (ATM and RAD3 related) are DNA damage-activated kinases that response to specific (and different) types of DNA lesions. ATM responds to DNA double strand breaks while ATR responds to replication protein A (RPA)-coated single strand DNA. In response to DNA damage ATM is activated by the MRN complex and is converted from an inactive dimer to an active kinase that phosphorylates numerous substrates including p53 and Chk2 to activate apoptosis, or to initiate cell cycle arrest. In contrast, inresponse to DNA damage during replication, ATR is activated by TopBP1 in an ATRIP-dependent manner to phosphorylate various substrates including Claspin and Chk1 which promote cell cycle checkpoint activation. Although functional interactions between ATM and ATR have been suggested, these two related kinases function largely independently in response to different types of DNA damage. Inactivation of ATM can lead to neurodegeneration, while hypomorphic mutation of ATR can lead to neurdevelopmental defects and ATR-Seckel syndrome.

Figure 3. The cell cycle of cortical progenitors change during development

Cortical progenitors undergo symmetric divisions during E10-12 and at this stage have a long S-phase of around 8 hours. The transition to neurogenic divisions results in a shortened S-phase and as progenitors undergo differentiation the G1 phase lengthens. Chromatin states involving high mobility group A proteins are also important for maintaining an open chromatin conformation in early cortical progenitors. Genome maintenance is paramount in early-born apical neural progenitors, and an increased S-phase length likely allows enhanced genome surveillance to ensure a pristine genome. Cortical layers form progressively from E12; VZ is the ventricular zone. DNA repair via homologous recombination (HR) and non-homologous end-joining (NHEJ) is important to ensure genome integrity during progenitor proliferation and differentiation. Figure adapted from reference .

Figure 4. Defective DNA single strand break repair can result in syndrome with varied neuropathology

Single strand breaks are a frequent type of DNA lesion in the nervous system. These lesions are repaired by an XRCC1-mediated pathway that includes polymerase β and ligases to complete repair after end-processing factors process damaged DNA termini to faciliate ligation. Factors such as TDP1 processes 3’ termini and APTX processes 5’ lesions involving adenylation of DNA, while PNKP can process both 5’ and 3’ termini. Defects in APTX, TDP1 lead to human neurodegeneratiove syndromes while disruption of PNKP leads to microcephaly, not neurdegeneration. Notably, despite these factors participating in the same DNA repair pathway the resultant neuropathology is distinct.