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Our initial studies identified a differential utilization of each of the two types of double strand break repair pathways in different regions of the developing nervous system [PNAS 103: 10017-22, 2006]. We showed that homologous recombination (HR) function was confined to proliferating cells, while immature postmitotic differentiating cells preferentially utilized non-homologous end-joining (NHEJ). We further established that ATM was uniquely required for DNA damage-induced apoptosis in only the differentiating cells after DNA DSBs where NHEJ, but not HR, occurs. These data have been important for understanding the specific repair pathways required to prevent accumulation of DNA DSBs in the nervous system.
In contrast to DNA DSBs, damage to only one DNA strand activates a distinct repair pathway termed single strand break repair (SSBR), and mutations in components of this pathway can also lead to human neurodegenerative syndromes. However, SSBR syndromes lack extra-neurological phenotypes, underscoring the unique importance of this pathway in the nervous system. Two prominent syndromes resulting from loss of DNA SSBR capacity are ataxia with oculomotor apraxia (AOA1) and spinocerebellar ataxia with axonal neuropathy (SCAN1). The syndromes result from respective defects in the DNA repair enzymes tyrosyl phosphodiesterase 1 (TDP1) which cleaves topoisomerase I-DNA complexes and other DNA 3’-termini, and Aprataxin (APTX) which removes 5’-adenylated DNA intermediates at the DNA break to allow ligation to proceed. We generated models for AOA1 and SCAN1 to further define the requirements for these factors during nervous system function [Nature443: 713-718, 2006; EMBO J. 26:4720-31, 2007]. In parallel, we also determined the role of a central SSBR factor, Xrcc1 and found that inactivation of Xrcc1 lead to the loss of a specific sub-type of cerebellar neuron (interneurons) that had not previously been linked to DNA damage, thus revealing a novel target in the cerebellum for DNA repair deficiency [NatureNeuroscience 2009, In Press].