Genotypic and Phenotypic Variables Affect Meiotic Cell Cycle Progression, Tumor Ploidy, and Cancer-Associated Mortality in a brca2-Mutant Zebrafish Model.

L Mensah,J L Ferguson,H R Shive

doi:10.1155/2019/9218251

Abstract

Successful cell replication requires both cell cycle completion and accurate chromosomal segregation. The tumor suppressor BRCA2 is positioned to influence both of these outcomes, and thereby influence genomic integrity, during meiotic and mitotic cell cycles. Accordingly, mutations in BRCA2 induce chromosomal abnormalities and disrupt cell cycle progression in both germ cells and somatic cells. Despite these findings, aneuploidy is not more prevalent in BRCA2-associated versus non-BRCA2-associated human cancers. More puzzlingly, diploidy in BRCA2-associated cancers is a negative prognostic factor, unlike non-BRCA2-associated cancers and many other human cancers. We used a brca2-mutant/tp53-mutant cancer-prone zebrafish model to explore the impact of BRCA2 mutation on cell cycle progression, ploidy, and cancer-associated mortality by performing DNA content/cell cycle analysis on zebrafish germ cells, somatic cells, and cancer cells. First, we determined that combined brca2/tp53 mutations uniquely disrupt meiotic progression. Second, we determined that sex significantly influences ploidy outcome in zebrafish cancers. Third, we determined that brca2 mutation and female sex each significantly reduce survival time in cancer-bearing zebrafish. Finally, we provide evidence to support a link between BRCA2 mutation, tumor diploidy, and poor survival outcome. These outcomes underscore the utility of this model for studying BRCA2-associated genomic aberrations in normal and cancer cells.

Highlights

Generation of cell progeny lies at the heart of virtually all biological processes
BRCA2 participates in multiple processes that span from the G2 checkpoint in late G2 phase to cytokinesis in M phase, as described below
BRCA2 may participate in regulation of entry into mitosis after the G2 checkpoint [11, 12] and was found to be essential for protection of stalled replication forks [13]. These findings indicate that loss of functional BRCA2 severely disrupts both meiotic and mitotic cell cycles and has significant potential to destabilize genomic integrity

Summary

Introduction

Generation of cell progeny lies at the heart of virtually all biological processes Performing this fundamental cell behavior requires both completion of the cell cycle and faithful replication and segregation of chromosomal content. Both meiotic and mitotic cell cycles are governed by these principles, clear mechanistic differences exist (reviewed by Duro E and Marston AL [1]). The tumor suppressor gene BRCA functions in multiple pathways that affect both meiotic and mitotic cell cycles, and thereby genomic stability. These include homology-directed repair (HDR), replication fork maintenance, spindle assembly checkpoint (SAC), cytokinesis, and telomere homeostasis (reviewed by Venkitaraman AR [2]). Cells enter G2 phase with 4C DNA content and exit M phase with 2C DNA content

Methods

Results

Discussion

Conclusion