The objectives of this proposal are to understand the role of nucleosome structure in the initiation of DNA synthesis, and find a connection between modifications of the core histones and the cell cycle machinery that drives the transition from G1 to S phase. To this end, mutant core nucleosome components will be used in a series of genetic screens and in combination with known mutants in DNA replication to find out which gene products interact with histones to mediate DNA replication-specific changes in chromatin structure. In addition, new mutant histones will be generated that have defects in the initiation of DNA synthesis, either failing to allow access to the DNA replication machinery, or allowing constitutive, unregulated access. The studies outlined here address how chromatin is altered to accommodate DNA replication, and the consequences of failures in this process. Such defects will likely lead to aberrant chromatin structure. Heterochromatin abnormalities in cancer cells are well documented1, and could represent a mechanism for chromosomal rearrangements or otherwise contribute to tumorigenesis. 1. Dutrillaux, B. Gerbault-Seureau, M. and Zafrani, B. (1990) Characterization of chromosomal, anomalies in human breast cancer. A comparison of 30 paradiploid cases with few chromosome changes. Cancer Genetics and Cytogenetics 49, 203-217.
