Cyclin e deregulation promotes loss of specific genomic regions

Leonardo K. Teixeira, Xianlong Wang, Yongjiang Li, Susanna Ekholm-Reed, Xiaohua Wu, Pei Wang, Steven I. Reed

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

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 [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.

Original languageEnglish
Pages (from-to)1327-1333
Number of pages7
JournalCurrent Biology
Volume25
Issue number10
DOIs
StatePublished - 18 May 2015
Externally publishedYes

Fingerprint

Dive into the research topics of 'Cyclin e deregulation promotes loss of specific genomic regions'. Together they form a unique fingerprint.

Cite this