Sincennes Marie-Claude, Humbert Magali, Grondin Benoît, Lisi Véronique, Veiga Diogo F T, Haman André, Cazaux Christophe, Mashtalir Nazar, Affar El Bachir, Verreault Alain, Hoang Trang
Institute of Research in Immunology and Cancer, University of Montreal, Montreal, QC, Canada H3C 3J7; Molecular Biology Program, University of Montreal, Montreal, QC, Canada H1T 2M4;
Institute of Research in Immunology and Cancer, University of Montreal, Montreal, QC, Canada H3C 3J7;
Proc Natl Acad Sci U S A. 2016 Feb 2;113(5):1393-8. doi: 10.1073/pnas.1515071113. Epub 2016 Jan 13.
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.
致癌转录因子在急性白血病中通常被激活，并颠覆正常基因表达网络，将造血祖细胞重编程为白血病前期干细胞，T细胞急性淋巴细胞白血病（T-ALL）中的仅含LIM结构域2（LMO2）就是例证。这些癌蛋白是否干扰其他依赖DNA的过程在很大程度上尚未得到探索。在此，我们表明LMO2通过与三种必需的复制酶相互作用被招募到DNA复制起点：DNA聚合酶δ（POLD1）、DNA引发酶（PRIM1）和微小染色体维持蛋白6（MCM6）。此外，将LMO2拴系到合成DNA序列足以将这些序列转化为复制起点。接下来，我们探讨了LMO2在红系和胸腺细胞发育中的重要性，这两个谱系中细胞周期和分化紧密协调。降低红系祖细胞中的LMO2水平会延迟G1-S期进程并阻止促红细胞生成素依赖的细胞生长，同时促进终末分化。相反，在胸腺细胞中异位表达会诱导DNA复制并使这些细胞进入细胞周期，导致分化阻滞。我们的结果确定了LMO2在直接促进DNA合成和G1-S期进程中的新作用。
