HISTONE MODIFICATION FOR THE INITIATION OF DNA SYNTHESIS

该建议的目的是了解核小体结构在DNA合成启动中的作用，并找到核心组蛋白的修饰与驱动从G1期向S期转变的细胞周期机制之间的联系。为此，突变的核心核小体成分将被用于一系列的遗传筛选，并与DNA复制中的已知突变相结合，以找出哪些基因产物与组蛋白相互作用，以介导DNA复制中染色质结构的特异性变化。此外，将产生新的突变组蛋白，这些组蛋白在DNA合成的启动过程中存在缺陷，要么不允许进入DNA复制机制，要么允许结构性的、不受监管的访问。这里概述的研究涉及染色质如何改变以适应DNA复制，以及这一过程中失败的后果。这种缺陷很可能会导致染色质结构的异常。癌细胞中的异染色质异常被很好地记录下来，可能代表了染色体重排的一种机制，或者以其他方式促进了肿瘤的发生。1.杜崔罗，B.Gerbault-Seureau，M.和Zafrani，B.(1990)人类乳腺癌染色体异常的特征。染色体改变较少的30例同源二倍体的比较癌症遗传学和细胞遗传学49,203-217。

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.