Mouse models of DNA double-strand break repair and neurological disease

Abstract

The repair of DNA damage is essential for the prevention of disease. The DNA double-strand break (DSB) is a particularly hazardous lesion. DNA DSBs activate a coordinated cellular response involving cell cycle checkpoint activation and repair of the DNA break, or alternatively apoptosis. In the nervous system the inability to respond to DNA DSBs may lead to neurodegenerative disease or brain tumors. Therefore, understanding the DNA DSB response mechanism in the nervous system is of high importance for developing new treatments for neurodegeneration and cancer. In this regard, the use of mouse models represents an important approach for advancing our understanding of the biology of the DNA damage response in the nervous system.

Figure 1. DSB responses are linked to developmental stage in the central nervous system

The nervous system undergoes differentiation that follows a recurring pattern of proliferation (neural stem cells and progenitors), differentiation (post-mitotic neurons) and finally maturation. The differentiation status of neural cells determines the response to DNA damage and the repair and effector kinase that are activated. Proliferating cells use HR while NHEJ is the main repair pathways used by non-dividing cells. ATM appears to function in recently postmitotic neural cells, while ATR is required by proliferating cells. However, the functional overlap between these related kinases has yet to be fully elucidated. Both proliferating cells and immature, post-mitotic neural cells are highly susceptible to DNA damage induced apoptosis and this process requires the p53-Puma signaling pathway. Functionally important DNA repair or DNA damage signaling pathways, including those involving ATM/ATR, and in the mature nervous system are yet to be clearly defined.

Figure 2. Defects in DNA damage signaling can lead to neurological disease

The DNA DSB response involves a variety of different factors that activate DNA repair or DNA signaling. DNA DSBs are repaired by either non-homologous end-joining (NHEJ) or homologous recombination (HR); each pathway involves distinct molecular machinery. DNA damage is detected by sensors that involve the MRN complex and signaling effectors such as ATM or ATR that activate down-stream signaling that functions to activate cell cycle checkpoints or elimination of the cell via activation of apoptosis. When these processes are disrupted human syndromes that feature neuropathology can occur. Genetic manipulation of the mouse is being used to mimic these DNA damage defective syndromes. Representative human syndromes are listed that result from defective DNA damage responses together with comparative phenotypes that occur in mouse models.