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bioRxiv · 10.1101/576082

Nbs1 Mediates Assembly and Activity of the Mre11 complex

Kim, J. H.·Penson, A. V.·Taylor, B. S.·Petrini, J.
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Abstract

We derived a mouse model in which a mutant form of Nbs1 (Nbs1mid8) exhibits severely impaired binding to the Mre11-Rad50 core of the Mre11 complex. The Nbs1mid8 allele was expressed exclusively in hematopoietic lineages (in Nbs1-/mid8vav mice). Unlike Nbs1flox/floxvav mice, which are Nbs1 deficient in the bone marrow, Nbs1-/mid8vav mice were viable. Nbs1-/mid8vav hematopoiesis was profoundly defective, exhibiting reduced cellularity of thymus and bone marrow, and stage specific blockage of B cell development. Within six months, Nbs1-/mid8 mice developed highly penetrant T cell leukemias. Nbs1-/mid8vav leukemias recapitulated mutational features of human T-ALL, containing mutations in Notch1, Trp53, Bcl6, Bcor, and Ikzf1, suggesting that Nbs1mid8 mice may provide a venue to examine the relationship between the Mre11 complex and oncogene activation in the hematopoietic compartment. Genomic analysis of Nbs1-/mid8vav malignancies showed focal amplification of 9qA2, causing overexpression of MRE11 and CHK1. We propose that overexpression compensates for the meta-stable Mre11-Nbs1mid8 interaction, and that selection pressure for overexpression reflects the essential role of Nbs1 in promoting assembly and activity of the Mre11 complex.

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Kim, J. H., Penson, A. V., Taylor, B. S., Petrini, J.. 2019-03-13. Nbs1 Mediates Assembly and Activity of the Mre11 complex. https://doi.org/10.1101/576082

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