title: Cyclin E deregulation promotes loss of specific genomic regions.
abstract: 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. Cyclin E normally accumulates at the G1/S boundary, where it promotes S phase entry and progression by activating Cdk2. In normal cells, cyclin E/Cdk2 activity is associated with DNA replication-related functions. However, deregulation of cyclin E leads to inefficient assembly of pre-replication complexes, replication stress, and chromosome instability. In malignant cells, cyclin E is frequently overexpressed, correlating with decreased survival in breast cancer patients. Transgenic mice deregulated for cyclin E in the mammary epithelia develop carcinoma, 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 cancer.
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Leonardo K
authors.initials: LK
authors.lastname: Teixeira
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Xianlong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Yongjiang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Susanna
authors.initials: S
authors.lastname: Ekholm-Reed
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Wu
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Pei
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: sreed@scripps.edu.
authors.forename: Steven I
authors.initials: SI
authors.lastname: Reed
mesh_terms: D000705:Anaphase / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication; D004847:Epithelial Cells / Q000502:physiology; D005260:Female; D056426:Genetic Loci; D042822:Genomic Instability; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006801:Humans; D008938:Mitosis; D005810:Multigene Family; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051562:Proto-Oncogene Proteins c-bcr / Q000235:genetics
chemical_list: C475820:CCNE1 protein, human; D019927:Cyclin E; C497422:KMT2A protein, human; D015513:Oncogene Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr