Abstract
BackgroundGenomic instability is a hallmark of cancer. Cancer progression depends on the development and amplification of mutations that alter the cellular response to threats to the genome. This can lead to DNA replication stress and the potential loss of genetic integrity of the newly formed cells. This study utilised fission yeast to map the interactions occurring in some of the most crucial pathways in both DNA replication and checkpoint monitoring involving Rad4, the Schizosaccharomyces pombe (S. pombe) TopBP1 homologue. We have modelled conditions of replication stress in the genetically tractable fission yeast, S. pombe using the hypomorphic rad4-116 allele. Synthetic genetic analysis was used to identify processes required for cell survival under conditions of DNA replication stress. With the aim of mapping the genetic interactions of rad4 and its mutant allele, rad4-116, several genes that could have an interaction with rad4 during replication stress have emerged as attractive. ResultsInteractions with genes involved in chromatin remodelling, such as hip1, and replication fork stalling resolution, such as mrc1, swi1 and swi3 were explored and confirmed. The interactions of Rad4 with each of the genes provided separate and distinct tumour formation pathways, as evident in the synthetically lethal interactions. Even within the same complex, rad4-116 double mutants behaved differently proving that Rad4 interacts at different levels and functions with the same proteins. ConclusionResults from this study provide a novel view of the rad4 interactions, the association of Rad4 with the replisome. The study also provides the groundwork on a theoretical and practical level for the exploration and separation of interactions of TopBP1 with the histone chaperone family and the replisome.
Highlights
IntroductionCancer progression depends on the development and amplification of mutations that alter the cellular response to threats to the genome
Genomic instability is a hallmark of cancer
Synthetic lethality on agar The aim of the experiment was to investigate the interactions between rad4 and hip1 which is implicated in the maintenance of chromatin structure and remodelling
Summary
Cancer progression depends on the development and amplification of mutations that alter the cellular response to threats to the genome This can lead to DNA replication stress and the potential loss of genetic integrity of the newly formed cells. The cell division cycle process has been linked to a wide variety of physiologic processes such as embryonic development and cell growth and pathologic processes such as cancer and Alzheimer’s disease [2] This occurs as errors or defects in genes which play a role in DNA replication, DNA repair, or checkpoint response have been highlighted to play a key role in the predisposition to cancer [3, 4]. It can be viewed as an important event that is common across all cancer types to the point that it has been proposed as a hallmark of cancer [6]
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