Carcinogenesis is frequently associated with the failure to regulate the cell cycle at the transition from G1 into S phase. This key periodic event coincides with the transcription of genes that encode the essential chromosomal proteins, histones. At this transition point, histone synthesis must be regulated both temporally and quantitatively to ensure faithful chromosome segregation later in the cell cycle during M phase. The transcription pattern of yeast histone genes has been exploited to identify novel regulatory factors that act at the G1-S phase boundary. Mutations in four regulatory genes (HIR, histone regulation) have been identified, and three of the wild type genes have been isolated. Each mutation derepresses transcription during the cell cycle by affecting factors that act at two regulatory sites in a histone gene promoter. One group of genes (HIR1, HIR2, HIR3) encode proteins that can be characterized as repressors that act a negative site. Two of the proteins (Hir1 and Hir2) do not contact DNA directly, and the hypothesis that they function as co-repressors will be tested. The product of a fourth gene (HIR4) acts at the histone-specific activation elements (UAS) to relieve repression by the negative site. The hypothesis that this gene product functions as an anti-repressor will be tested. Quantitative regulation of histone synthesis has been found to occur through the novel phenomenon of autoregulation; histones H2A and H2B regulate transcription of one HTAHTB locus through many of the same factors that regulate periodic transcription. The hypothesis that autoregulation occurs by interaction between H2A and the product of a HIR gene will be tested.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM040118-06A1
Application #
3297478
Study Section
Microbial Physiology and Genetics Subcommittee 2 (MBC)
Project Start
1988-04-01
Project End
1997-08-31
Budget Start
1993-09-27
Budget End
1994-08-31
Support Year
6
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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