The LMO2 oncogene regulates DNA replication in hematopoietic cells
| Autor: | Benoit Grondin, Trang Hoang, Marie-Claude Sincennes, Nazar Mashtalir, EL Bachir Affar, Magali Humbert, Alain Verreault, Christophe Cazaux, André Haman, Diogo F.T. Veiga, Véronique Lisi |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
DNA re-replication DNA Replication Eukaryotic DNA replication Replication Origin Pre-replication complex DNA polymerase delta S Phase DNA replication factor CDT1 03 medical and health sciences Mice 0302 clinical medicine Control of chromosome duplication hemic and lymphatic diseases Animals Adaptor Proteins Signal Transducing Multidisciplinary biology DNA replication Biological Sciences LIM Domain Proteins Hematopoietic Stem Cells 030104 developmental biology 030220 oncology & carcinogenesis biology.protein Cancer research Origin recognition complex |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| DOI: | 10.1073/pnas.1515071113 |
| Popis: | Oncogenic transcription factors are commonly activated in acute leukemias and subvert normal gene expression networks to reprogram hematopoietic progenitors into preleukemic stem cells, as exemplified by LIM-only 2 (LMO2) in T-cell acute lymphoblastic leukemia (T-ALL). Whether or not these oncoproteins interfere with other DNA-dependent processes is largely unexplored. Here, we show that LMO2 is recruited to DNA replication origins by interaction with three essential replication enzymes: DNA polymerase delta (POLD1), DNA primase (PRIM1), and minichromosome 6 (MCM6). Furthermore, tethering LMO2 to synthetic DNA sequences is sufficient to transform these sequences into origins of replication. We next addressed the importance of LMO2 in erythroid and thymocyte development, two lineages in which cell cycle and differentiation are tightly coordinated. Lowering LMO2 levels in erythroid progenitors delays G1-S progression and arrests erythropoietin-dependent cell growth while favoring terminal differentiation. Conversely, ectopic expression in thymocytes induces DNA replication and drives these cells into cell cycle, causing differentiation blockade. Our results define a novel role for LMO2 in directly promoting DNA synthesis and G1-S progression. |
| Databáze: | OpenAIRE |
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