The challenging task of replicating a eukaryotic genome is made more difficult by intrinsic and extrinsic agents that interrupt DNA replication. To cope with these difficulties, cells have a DNA replication monitoring system that senses stalled replication forks and direct various responses. One of these responses is the S-M checkpoint that delays the onset of mitosis (M) while DNA synthesis (S) is underway. Other responses control DNA replication, repair and recombination. These responses are collectively termed the replication checkpoint. This application proposes to use the fission yeast Schizosaccharomyces pombe to investigate the replication checkpoint. Fission yeast has played a pioneering role in the discovery and analysis of checkpoint mechanisms that are conserved amongst all eukaryotes, including humans. The studies will focus on he protein kinase Cds1, a major effector of the checkpoint.
One aim i s to understand how Cds1 is regulated. These studies will concentrate on Mrc1, a protein then channels the replication checkpoint signal from the sensor kinase Rad3 to Cds1.
The second aim i s to understand how stalled replication forks are stabilized. Proteins involved in this process I will be identified and analyzed.
The third aim i s to characterize Cds1 targets. These studies will focus on Mus81 and Eme1, components of a Holliday junction resolvase that cleaves X-structured DNA. All of these genes have confirmed or presumptive homologs in humans. Some of these homologs are known to be important for maintaining genome integrity and preventing cancer, but how they accomplish this task is largely unknown. It is anticipated that studies of the replication checkpoint in fission yeast will provide a valuable framework for understanding replication checkpoint control in humans.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Cell Development and Function Integrated Review Group (CDF)
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Zatz, Marion M
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Scripps Research Institute
La Jolla
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Zhu, Min; Zhao, Hongchang; Limbo, Oliver et al. (2018) Mre11 complex links sister chromatids to promote repair of a collapsed replication fork. Proc Natl Acad Sci U S A 115:8793-8798
Zhao, Hongchang; Zhu, Min; Limbo, Oliver et al. (2018) RNase H eliminates R-loops that disrupt DNA replication but is nonessential for efficient DSB repair. EMBO Rep 19:
Ganguly, Abantika; Guo, Lan; Sun, Lingling et al. (2018) Tdp1 processes chromate-induced single-strand DNA breaks that collapse replication forks. PLoS Genet 14:e1007595
Limbo, Oliver; Yamada, Yoshiki; Russell, Paul (2018) Mre11-Rad50-dependent activity of ATM/Tel1 at DNA breaks and telomeres in the absence of Nbs1. Mol Biol Cell 29:1389-1399
Sanchez, Arancha; Gadaleta, Mariana C; Limbo, Oliver et al. (2017) Lingering single-strand breaks trigger Rad51-independent homology-directed repair of collapsed replication forks in the polynucleotide kinase/phosphatase mutant of fission yeast. PLoS Genet 13:e1007013
Reubens, Michael C; Rozenzhak, Sophie; Russell, Paul (2017) Multi-BRCT Domain Protein Brc1 Links Rhp18/Rad18 and ?H2A To Maintain Genome Stability during S Phase. Mol Cell Biol 37:
Guo, Lan; Ganguly, Abantika; Sun, Lingling et al. (2016) Global Fitness Profiling Identifies Arsenic and Cadmium Tolerance Mechanisms in Fission Yeast. G3 (Bethesda) 6:3317-3333
Jensen, Kristi L; Russell, Paul (2016) Ctp1-dependent clipping and resection of DNA double-strand breaks by Mre11 endonuclease complex are not genetically separable. Nucleic Acids Res 44:8241-9
Petersen, Janni; Russell, Paul (2016) Growth and the Environment of Schizosaccharomyces pombe. Cold Spring Harb Protoc 2016:pdb.top079764
Sánchez, Arancha; Russell, Paul (2015) Ku stabilizes replication forks in the absence of Brc1. PLoS One 10:e0126598

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