Lombraña Rodrigo, Almeida Ricardo, Álvarez Alba, Gómez María
Functional Organization of the Genome Group, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas/Universidad Autónoma de Madrid , Madrid, Spain.
Front Genet. 2015 Apr 28;6:158. doi: 10.3389/fgene.2015.00158. eCollection 2015.
The unanticipated widespread occurrence of stable hybrid DNA/RNA structures (R-loops) in human cells and the increasing evidence of their involvement in several human malignancies have invigorated the research on R-loop biology in recent years. Here we propose that physiological R-loop formation at CpG island promoters can contribute to DNA replication origin specification at these regions, the most efficient replication initiation sites in mammalian cells. Quite likely, this occurs by the strand-displacement reaction activating the formation of G-quadruplex structures that target the origin recognition complex (ORC) in the single-stranded conformation. In agreement with this, we found that R-loops co-localize with the ORC within the same CpG island region in a significant fraction of these efficient replication origins, precisely at the position displaying the highest density of G4 motifs. This scenario builds on the connection between transcription and replication in human cells and suggests that R-loop dysregulation at CpG island promoter-origins might contribute to the phenotype of DNA replication abnormalities and loss of genome integrity detected in cancer cells.
近年来，人类细胞中意外广泛出现的稳定杂交DNA/RNA结构（R环）以及越来越多证据表明其与多种人类恶性肿瘤有关，这激发了对R环生物学的研究。在此，我们提出在CpG岛启动子处生理性R环的形成有助于这些区域（哺乳动物细胞中最有效的复制起始位点）的DNA复制起点的确定。很可能，这是通过链置换反应激活G-四链体结构的形成来实现的，这些G-四链体结构以单链构象靶向起始识别复合物（ORC）。与此一致的是，我们发现在这些高效复制起点的很大一部分中，R环与ORC在同一CpG岛区域内共定位，恰好位于显示G4基序最高密度的位置。这种情况建立在人类细胞中转录与复制之间的联系之上，并表明CpG岛启动子-起点处的R环失调可能导致癌细胞中检测到的DNA复制异常和基因组完整性丧失的表型。
