Academic journal article Genetics

The Transient Inactivation of the Master Cell Cycle Phosphatase Cdc14 Causes Genomic Instability in Diploid Cells of Saccharomyces Cerevisiae

Academic journal article Genetics

The Transient Inactivation of the Master Cell Cycle Phosphatase Cdc14 Causes Genomic Instability in Diploid Cells of Saccharomyces Cerevisiae

Article excerpt

GENOMIC instability is one of the hallmarks of cancer cells. Many genomic alterations result in gene dose variation including deletions/duplication, gross chromosomal rearrangements (GCRs), and aneuploidy; loss of heterozygosity (LOH) associated with mitotic recombination is also observed (Hanahan and Weinberg 2011). In wild-type cells, specialized mechanisms exist, such as cell cycle checkpoints and DNA repair activities, which suppress genome instability. Genes encoding for proteins that protect cells from cancer-related genomic instability are referred to as caretakers. Many of the tumor suppressor genes identified in familiar cancer-prone syndromes are caretakers. Although caretakers are not directly responsible for the decision of a cell to divide, their loss leads cells to rapidly accumulate genomic aberrations and mutations that potentially result in disorganization of cell division and their subsequent transformation into cancer cells (Kinzler and Vogelstein 1997; van Heemst et al. 2007). For example, mutations in genes involved in DNA repair pathways such as nonhomologous end joining, homologous recombination, mismatch repair, base excision repair, and nucleotide excision repair have been shown to lead to the accumulation of mutations within the genome that significantly increase the risk of carcinogenesis (Negrini et al. 2010; Aguilera and García-Muse 2013).

Whereas the effects of the permanent loss of caretakers have been extensively studied, less is known about the consequences that a transient loss of function of a caretaker might have on the cell fate. One study, however, reported that the transient loss of the helicase Bloom syndrome protein (BLM) activity leads to a significant increase in LOH events throughout the genome in mouse cell lines, pointing out a role of the BLM dysfunction in the early steps of tumorigenesis (Yamanishi et al. 2013). In addition, it has been also shown that the transient inactivation of the BRCA2- and CDKN1A(p21)-interacting protein BCCIP is sufficient to promote tumorigenesis. Permanent loss of BCCIP does not result in tumorigenesis. This apparent discrepancy is consistent with the observation that the activity of BCCIP is required for the later steps of tumor progression (Huang et al. 2013).

The yeast Saccharomyces cerevisiae has been used as a model organism to understand the molecular functions of caretakers. Since yeast cells can tolerate most loss-offunction caretaker genes, most studies of the effects of these genes on genome stability have been carried out using strains with permanent inactivating mutations. Nevertheless, it is presumed from the molecular function that many essential genes related to the cell cycle progression must be caretakers as well. Although their essential role for cell division precludes the analysis of strains with null mutations, transient inactivation of the protein function might still be possible and might have destabilizing effects on the genome. One clear candidate for such a gene in yeast is the cell cycle phosphatase CDC14, which is essential for the mitosis-to-G1 transition (Stegmeier and Amon 2004), and whose transient loss in haploids leads to irresolvable anaphase bridges (Machín et al. 2006; Quevedo et al. 2012). CDC14 was first identified by Culotti and Hartwell (1971) in their screening for genes that regulate the cell cycle in the yeast S. cerevisiae. This protein belongs to a superfamily of dual-specific phosphatases highly conserved during evolution, from yeasts to humans, that preferentially dephosphorylate cyclin-dependent kinase (CDK) targets (Mocciaro and Schiebel 2010).

The clearest molecular role for Cdc14 in the maintenance of the yeast genome is related to its function in resolving sister-chromatid linkages that preclude their segregation during anaphase. Indeed, timely Cdc14 activity is essential to ensure the proper segregation of the ribosomal DNA array (rDNA) (D'Amours et al. 2004; Stegmeier and Amon 2004; Sullivan et al. …

Search by... Author
Show... All Results Primary Sources Peer-reviewed

Oops!

An unknown error has occurred. Please click the button below to reload the page. If the problem persists, please try again in a little while.