03 September 2012

CPR scientist generates new insight into a serious neurodegenerative disease

The ‘Chromatin Structure and Function’ research group have studied the rare cancer-prone neurodegenerative disease A-T (Ataxia telangiectasia) that causes severe disability in patients during childhood. A-T is caused by mutations in the gene coding for the ATM protein - a key signaling kinase in response to DNA breaks that regulates DNA repair, cell cycle checkpoints, and apoptosis - resulting in a non-functional ATM protein. To determine whether the functions of ATM are mediated solely by its kinase activity, Daniel et al. generated two mouse models containing single, catalytically inactivating point mutations in ATM. They show here that single point mutations disrupting the kinase activity of ATM lead to early embryonic lethality in mice. These results reveal a previously unknown essential role for ATM kinase activity during embryonic development and provide a potential explanation for why missense mutations with no detectable kinase activity are rarely found in patients with classical A-T. They propose that ATM kinase-inactive missense mutations, unless otherwise compensated for, interfere with the homologous recombination DNA repair pathway during embryogenesis. Furthermore, the finding that inhibition of ATM kinase activity in vivo does not always equate to complete loss of ATM protein suggests that treatments using pharmacological ATM inhibitors could be more toxic than previously anticipated. Results are published in J Cell Biol and are in addition highlighted in a review by Shiloh Y et. al also in J Cell Biol.