Eukaryotic cells have developed a series of cellular """"""""checkpoints"""""""" that sense the presence of damaged DNA and cause a delay in cell cycle progression to ensure that genetic information is faithfully transferred to progeny cells. Failure of checkpoint genes to halt cell cycle progression can lead to improper chromosomal segregation, segregation of damaged chromosomes, and replication of damaged chromosomes. Several human checkpoint genes map to chromosomal regions implicated m the etiology of a variety of cancers including small cell lung carcinoma, duodenal adenocarcinoma, head and neck squamous cell carcinoma, bladder cancer, and colon cancer. An understanding of checkpoint function will shed light on the mechanism of tumor formation and cancer predisposition and may provide insights into new therapeutic targets for cancer treatment. The high level of conservation between human and yeast checkpoint genes makes the budding yeast, Saccharomyces cerevisiae, an ideal organism for studying checkpoints. In budding yeast, RAD17, RAD24, MEC3, and DDC1 are required for detecting damaged DNA and activating the checkpoint response. It is currently not known how this is accomplished. The proposed studies will determine how these sensor genes recognize damaged DNA and generate the checkpoint signal with biochemical and genetic studies that define protein-DNA interactions and protein-protein interactions among sensor proteins. Identifying direct interactions among the sensor proteins and determining whether these interactions are important for recognizing specific DNA structures or modulating the structure of damaged DNA will be crucial to understand how sensor genes function in establishing the checkpoint.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32GM020648-02
Application #
6385231
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Wolfe, Paul B
Project Start
2000-07-01
Project End
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
2
Fiscal Year
2001
Total Cost
$34,832
Indirect Cost
Name
Brandeis University
Department
Type
Organized Research Units
DUNS #
616845814
City
Waltham
State
MA
Country
United States
Zip Code
02454