西亚试剂 ：Co-transcriptional DNA and RNA Cleavage during Type III

Cell-cycle progression is regulated by the cyclin-dependent kinase (Cdk) family of protein kinases, so named because their activation depends on association with regulatory subunits known as cyclins [ 1 ]. Cyclin E normally accumulates at the G1/S boundary, wher it promotes S phase entry and progression by activating Cdk2. In normal cells, cyclin E/Cdk2 activity is associated with DNA replication-related functions [ 2 ]. However, deregulation of cyclin E leads to inefficient assembly of pre-replication complexes [ 3 ], replication stress [ 4 ], and chromosome instability [ 5 ]. In malignant cells, cyclin E is frequently overexpressed, correlating with decreased survival in breast cancer patients [ 6, 7 ]. Transgenic mice deregulated for cyclin E in the mammary epithelia develop carcinoma [ 8 ], confirming that cyclin E is an oncoprotein. However, it remains unknown how cyclin E-mediated replication stress promotes genomic instability during carcinogenesis. Here, we show that deregulation of cyclin E causes human mammary epithelial cells to enter into mitosis with short unreplicated genomic segments at a small number of specific loci, leading to anaphase anomalies and ultimately deletions. Incompletely replicated regions are preferentially located at late-replicating domains, fragile sites, and breakpoints, including the mixed-lineage leukemia breakpoint cluster region (MLL BCR). Furthermore, these regions are characterized by a paucity of replication origins or unusual DNA structures. Analysis of a large set of breast tumors shows a significant correlation between cyclin E amplification and deletions at a number of the genomic loci identified in our study. Our results demonstrate how oncogene-induced replication stress contributes to genomic instability in human cance以上资料由西亚试剂：http://www.xiyashiji.com/