Nbn−Mre11 interaction is required for tumor suppression and genomic integrity Journal Article
| Authors: | Kim, J. H.; Penson, A. V.; Taylor, B. S.; Petrini, J. H. J. |
| Article Title: | Nbn−Mre11 interaction is required for tumor suppression and genomic integrity |
| Abstract: | We derived a mouse model in which a mutant form of Nbn/ Nbs1mid8 (hereafter Nbnmid8) exhibits severely impaired binding to the Mre11−Rad50 core of the Mre11 complex. The Nbnmid8 allele was expressed exclusively in hematopoietic lineages (in Nbn−/mid8vav mice). Unlike Nbnflox/floxvav mice with Nbn deficiency in the bone marrow, Nbn−/mid8vav mice were viable. Nbn−/mid8vav mice hematopoiesis was profoundly defective, exhibiting reduced cellularity of thymus and bone marrow, and stage-specific blockage of B cell development. Within 6 mo, Nbn−/mid8 mice developed highly penetrant T cell leukemias. Nbn−/mid8vav leukemias recapitulated mutational features of human T cell acute lymphoblastic leukemia (T-ALL), containing mutations in NOTCH1, TP53, BCL6, BCOR, and IKZF1, suggesting that Nbnmid8 mice may provide a venue to examine the relationship between the Mre11 complex and oncogene activation in the hematopoietic compartment. Genomic analysis of Nbn−/mid8vav malignancies showed focal amplification of 9qA2, causing overexpression of MRE11 and CHK1. We propose that overexpression of MRE11 compensates for the metastable Mre11−Nbnmid8 interaction, and that selective pressure for overexpression reflects the essential role of Nbn in promoting assembly and activity of the Mre11 complex. © 2019 National Academy of Sciences. All rights reserved. |
| Keywords: | controlled study; gene mutation; gene deletion; clinical feature; nonhuman; genetic analysis; protein function; animal cell; mouse; rad50 protein; allele; gene; gene overexpression; gene amplification; bone marrow; protein protein interaction; animal experiment; animal model; protein binding; protein p53; acute lymphoblastic leukemia; b lymphocyte; cell lineage; nibrin; cancer inhibition; oncogene; gene activation; thymus; genomic instability; hematopoietic cell; dna damage response; hematopoiesis; protein bcl 6; checkpoint kinase 1; t cell leukemia; ikaros transcription factor; mutant; notch1 receptor; penetrance; tumor suppression; chromosome 9q; tp53 gene; bcl6 gene; human; priority journal; article; ikzf1 gene; notch1 gene; nbn−mre11 interaction; double strand break repair protein mre11; bcor gene |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 116 |
| Issue: | 30 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2019-07-23 |
| Start Page: | 15178 |
| End Page: | 15183 |
| Language: | English |
| DOI: | 10.1073/pnas.1905305116 |
| PUBMED: | 31285322 |
| PROVIDER: | scopus |
| PMCID: | PMC6660787 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 4 September 2019 -- Source: Scopus |
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