The Mre11 complex (Mre11, Rad50 and Nbs1) occupies a central node of the DNA damage response (DDR) network, and is required for ATM activation in response to DNA damage. Hypomorphic alleles of MRE11 and NBS1 confer embryonic lethality in ATM deficient mice, indicating that the complex exerts ATM independent functions that are essential when ATM is absent. To delineate those functions, a conditional ATM allele (ATMflox) was crossed to hypomorphic NBS1 mutants (Nbs1ΔB/ΔB mice). Nbs1ΔB/ΔB Atm−/− hematopoietic cells derived by crossing to vavcre were viable in vivo. Nbs1ΔB/ΔB Atm−/− VAV mice exhibited a pronounced defect in double strand break (DSB) repair, and completely penetrant early onset lymphomagenesis. In addition to repair defects observed, fragile site instability was noted, indicating that the Mre11 complex promotes genome stability upon replication stress in vivo. The data suggest combined influences of the Mre11 complex on DNA repair, as well as the responses to DNA damage and DNA replication stress.

<p>Nbs1deltaB/deltaB Atm -/- immortalized MEFs show inability to form colonies at atmospheric oxygen levels.</p>

<div>Abstract<p>The Mre11 complex (Mre11, Rad50, and Nbs1) occupies a central node of the DNA damage response (DDR) network and is required for ATM activation in response to DNA damage. Hypomorphic alleles of <i>MRE11</i> and <i>NBS1</i> confer embryonic lethality in ATM-deficient mice, indicating that the complex exerts ATM-independent functions that are essential when ATM is absent. To delineate those functions, a conditional ATM allele (<i>ATM^flox</i>) was crossed to hypomorphic <i>NBS1</i> mutants (<i>Nbs1^ΔB/ΔB</i> mice). <i>Nbs1^ΔB/ΔB Atm</i>^−/− hematopoietic cells derived by crossing to <i>vav^cre</i> were viable <i>in vivo</i>. <i>Nbs1^ΔB/ΔB Atm</i>^−/− <i>^VAV</i> mice exhibited a pronounced defect in double-strand break repair and completely penetrant early onset lymphomagenesis. In addition to repair defects observed, fragile site instability was noted, indicating that the Mre11 complex promotes genome stability upon replication stress <i>in vivo</i>. The data suggest combined influences of the Mre11 complex on DNA repair, as well as the responses to DNA damage and DNA replication stress.</p><p><b>Implications:</b> A novel mouse model was developed, by combining a <i>vav^cre</i>-inducible ATM knockout mouse with an <i>NBS1</i> hypomorphic mutation, to analyze ATM-independent functions of the Mre11 complex <i>in vivo</i>. These data show that the DNA repair, rather than DDR signaling functions of the complex, is acutely required in the context of ATM deficiency to suppress genome instability and lymphomagenesis. <i>Mol Cancer Res; 14(2); 185–95. ©2015 AACR</i>.</p></div>