rhind

Office: LRB 904
Phone: 508.856.8316
nick.rhind@umassmed.edu

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Nick Rhind, Ph.D.

KW-science

Professor 
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Graduate School of Biomedical Sciences
    Biochemistry and Molecular Pharmacology
    Interdisciplinary Graduate Program
    

Programs, Centers and Institutes
   Bioinformatics and Integrative Biology
   Cancer Center

 


DNA Replication and Replication Checkpoints


A major current interest of my lab is how replication is regulated during S phase. We are interested both in how normal S phase is organized to insure efficient replication of the entire genome, and how cells respond to DNA damage during S phase to coordinate replication and repair. 

Most of the work in my lab focuses on the fission yeast Schizosaccharomyces pombe. Fission yeast is a great organism for studying replication because it has a simple, well-understood cell cycle and is amenable to genetic, molecular and biochemical approaches. It has the added attraction that the mechanisms of cell cycle and checkpoint control in fission yeast are very similar to those used by human cells. In fact, much of what is known about human cell cycle and checkpoints was first discovered in yeast. My lab is currently pursuing two general areas of the regulation of replication. 

Regulation of Origin Firing Kinetics 
Eukaryotic genomes replicate in defined patterns, with some parts of the genome replicating early in S phase and other parts replicating later. Replication timing correlates with transcription, chromatin modification, sub-nuclear localization and genome evolution, suggesting an intimate association between replication timing and other important aspects of chromosome metabolism. However, the mechanism of replication timing is currently unknown. 

We developed an computational approach to extract replication kinetics from genome-wide replication time courses. Our results support a model where earlier-firing origins have more MCM complexes loaded and a more-accessible chromatin environment. The MCM complex is the replicative helicase; its loading is what establishes sites as potential replication origins. We propose that the timing of origin firing is regulated in by the number of MCM complexes loaded at an origin. Thus, for the first time, our model suggests a detailed, testable, biochemically plausible mechanism for the regulation of replication timing in eukaryotes. ChIP-seq validation of our model confirms that early firing origins have more MCM loaded. We are currently exploring how MCM loading is regulated at different origins. 

Checkpoint Regulation of Replication 
Checkpoints are mechanisms that cells use to deal with problems during the cell cycle, such as DNA damage, replication errors and misattachment of chromosomes to the mitotic spindle. By actively responding to these problems, cells can fix most of them. In contrast, cells that lack proper checkpoints are very sensitive to DNA damage and show increased rates of mutation and other chromosomal abnormalities. Loss of checkpoints is an important step in the development of cancer. 

The S-phase DNA damage checkpoint slows the rate of replication in response to DNA damage. The simple model is that this checkpoint prevents damaged DNA from being replicated before it is repaired. However, the checkpoint is clearly more subtle than that. Recent results from yeast and human cells suggest that this checkpoint coordinates recombinational repair and replication during S-phase. In particular, we have established an epistatic pathway of recombinational-repair proteins that regulate replication-fork progress in response to DNA damage. We think this pathway regulates a choice the fork makes when it encounters damage: it can replicate quickly in an error-prone manner or, via a checkpoint-dependent mechanism, it can use recombinational strand switching to replicate the damaged template accurately, but slowly. Furthermore, via phospho-proteomics, we have identified candidate checkpoint targets, which maybe responsible for making this decision.

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