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We have now commenced an examination of the role of NHEJ proteins (DNA ligase IV in particular) during development. Since LIG4 Syndrome patients display growth delay and microcephaly, we examined how deficiency in LigIV impacts on embryonic neurogenesis. The embryonic brain is also highly sensitive to ionising riadiation – so we probed the basis underlying this sensitivity. Our findings (soon to be published) show that the embryonic brain is highly sensitive to DSB induced apoptosis. In the stem/early progenitor cells, apoptosis has a contribution from ATM but also arises via an ATM-independent process. The  replicating stem cell region is the region most sensitive to apoptosis. But in the LigIV-deficient mouse, apoptosis arises in both the replicating region and in the differentiated layer (called the intermediate zone).  We propose the DSBs arise during replication in the rapidly dividing stem cells and require DNA ligase IV for effiicient repair – in LigIV deficient mice, cells with unrepaired DSBs can pass through an inefficient G2/M checkpoint and undergo apoptosis in the differentiated intermediate zone. The differentiated zone appears highly sensitive to a low number of persistent DSBs whereas the layer with the stem cells is highly sensitive to DSB induction after radiation exposure.