CELL CYCLE CHECKPOINT CONTROL IN RESPONSE TO DNA DAMAGE

Project Details

Description

The presence of a mechanism which monitors the integrity of the genome
and leads to cell cycle arrest in the event of DNA damage has been
described as checkpoint control. Failure to arrest the cell cycle when
DNA is damaged can lead to the propagation of mutations or loss of
chromosomal material. While the phenomena of cell cycle arrest before DNA
replication (G1 arrest) or after DNA replication (G2 arrest) is well-
established, the signal transduction pathway which couples the detection
of DNA damage to control of progression through the cell cycle is only
beginning to be elucidated. The proposed project aims to characterize the
checkpoint which leads to cell cycle arrest prior to mitosis in response
to DNA damage, initially through the characterization of the chk1 protein
kinase (p56chk1) in Schizosaccharomyces pombe. Cells which lack a
functional chk1 gene fail to arrest the cell cycle prior to mitosis when
DNA damage takes place, attempt to proceed through the cell cycle with
damaged DNA and subsequently die. The products of several other genes are
also required for cell cycle arrest in response to DNA damage; however,
despite knowledge of the primary sequence of the rad gene products,
little is known about their function. As a protein kinase, p56chk1 is an
ideal protein with which to initiate a mechanistic characterization of
this pathway. To determine the role of p56chk1 in mediating cell cycle
arrest following DNA damage, two complementary lines of research will be
carried out: biochemical studies to characterize the regulation of the
activity of p56chk1 and genetic screens to identify proteins with which
p56chk1 interacts.

The fission and budding yeasts have been used successfully as tools for
the identification of human genes which govern progression through the
cell cycle due to evolutionary conservation of the molecules involved.
The architecture of many signal transduction pathways has been conserved
as well. Thus, characterization of the p56chk1 dependent cell cycle
arrest pathway should prove to be a useful paradigm for dissecting the
pathway coupling detection of DNA damage to cell cycle arrest in human
cells. Information regarding the mechanism of cell cycle arrest will be
vital for the design of more effective ways of overriding the pathway for
chemotherapeutic treatment of tumor cells.
StatusFinished
Effective start/end date8/1/957/31/14

Funding

  • National Institute of General Medical Sciences
  • National Institute of General Medical Sciences: $346,161.00
  • National Institute of General Medical Sciences: $298,368.00
  • National Institute of General Medical Sciences: $388,912.00
  • National Institute of General Medical Sciences: $357,589.00
  • National Institute of General Medical Sciences: $385,491.00
  • National Institute of General Medical Sciences: $390,974.00
  • National Institute of General Medical Sciences: $434,428.00
  • National Institute of General Medical Sciences: $381,405.00
  • National Institute of General Medical Sciences: $20,619.00
  • National Institute of General Medical Sciences: $381,636.00
  • National Institute of General Medical Sciences: $390,885.00
  • National Institute of General Medical Sciences: $257,072.00
  • National Institute of General Medical Sciences: $48,106.00
  • National Institute of General Medical Sciences
  • National Institute of General Medical Sciences: $352,929.00
  • National Institute of General Medical Sciences
  • National Institute of General Medical Sciences
  • National Institute of General Medical Sciences

ASJC

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Genetics
  • Molecular Biology
  • Cell Biology

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