Cyclin E Deregulation Promotes Loss of Specific Genomic Regions

Abstract

Summary 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, 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 [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 cancer.

NFAT1 transcription factor regulates cell cycle progression and cyclin E expression in B lymphocytes

“…[18][19] Overexpression of Cyclin E interferes with pre-replication complex assembly, causing replication stress and genomic instability. [20][21][22][23] In malignant cells, deregulation of Cyclin E is associated with tumor development, aggressiveness, and poor outcome in different human cancers. [24][25][26][27][28] Transgenic mice models expressing high levels of Cyclin E in T lymphocytes are predisposed to lymphoid hyperplasia and malignant transformation, indicating a causative role for Cyclin E oncoprotein in lymphomas.…”

To break or not to break – context matters

“…9 While the 2 regions identified in this paper overlap with cyclin E-induced FSs in BJ-hTERT cells, most regions do not. This supports the notion that oncogeneinduced fragility depends on the combination of the specific aberrantly expressed oncogene and the cell type in which it is expressed.…”

The Role of the Transcriptional Response to DNA Replication Stress

“…However, this transcriptional response must be tightly regulated to prevent damaging effects. Inappropriate expression of individual E2F targets, including Cyclin E, Cdc6 and Cdt1, causes DNA replication stress and genome instability [47,55,111]. In addition, maintaining E2F-dependent transcription during S phase would result in increased transcription of many targets, which is likely to increase the chance of collisions between replication forks and transcriptional bubbles.…”