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Nicholas Rhind, Ph.D.
Academic Role: Assistant Professor
Faculty Appointment(s) In:
Biochemistry and Molecular Pharmacology
Other Affiliation(s):
Cell Biology
Interdisciplinary Graduate Program
Checkpoint Regulation of the Fission Yeast Cell Cycle
 The main
interest of my lab is checkpoint regulation of the cell cycle. 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.
Most of the work in my lab focuses on the fission yeast Schizosaccharomyces
pombe (Figure 1). S. pombe is a
great organism for studying checkpoint regulation 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 pombe are very similar to those used by human cells. In
fact, much of what is known about human cell cycle checkpoints was first discovered
in pombe. My lab is currently pursuing three general areas of checkpoint
regulation in pombe.
The G2 DNA damage and DNA replication checkpoints are two closely related
checkpoints that prevent cells from entering mitosis if DNA is damaged or incompletely
replicated (Figure 2). By preventing mitosis, the
checkpoints allow the cell to repair the damage or complete replication before dividing.
Attempting mitosis with broken or unreplicated chromosomes would be most
deleterious. While these checkpoints are understood at a broad level, the molecular
mechanisms remain to be worked out. One particularly interesting aspect is the
regulation of the mitotic inhibitor Mik1. Mik1 is a kinase that phosphorylates and
inhibits Cdc2, the master regulator of mitosis. Mik1 plays important roles in both
checkpoints, and is regulated by the checkpoints in at least three ways: at the level
of transcript accumulation, at the level of protein accumulation, and at the level of
enzyme activation. I am particularly interested to understand the transcriptional and
post-translation regulation of Mik1 abundance and how this regulation relates to
general checkpoint regulation of protein level.
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 pombe and human cells suggest that this checkpoint
may coordinate recombinational repair and replication during S-phase. We are
characterizing the requirements for recombinational machinery in the checkpoint and
using physical techniques to investigate the effect of the checkpoint on replication
origin use and fork elongation.
The G1 size control checkpoint prevents cells from entering S-phase when they are
too small. This raises the interesting question of how cells know how big they are.
Several genetic projects are underway to identify the genes involved in cell size
measurement and regulation, and to test various models of cell size control.
Office: Research 904, Lab 940D&E
Phone: 508-856-8316
E-mail: Nick.Rhind@umassmed.edu
Keywords:
Checkpoints,
DNA Recombination,
Cell Cycle,
DNA Replication,
Genetics
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55 Lake Avenue North Worcester, MA 01655