HISTONE MODIFICATION FOR THE INITIATION OF DNA SYNTHESIS

该提案的目标是了解核小体结构在DNA合成起始中的作用，并找到核心组蛋白修饰与驱动从G1期向S期过渡的细胞周期机制之间的联系。 为此，突变核心核小体组分将用于一系列遗传筛选，并与DNA复制中的已知突变体组合，以找出哪些基因产物与组蛋白相互作用，以介导染色质结构中的DNA复制特异性变化。 此外，将产生新的突变组蛋白，其在DNA合成的起始中具有缺陷，或者不能允许进入DNA复制机制，或者允许组成性的、不受调节的进入。这里概述的研究解决了染色质如何改变以适应DNA复制，以及在这个过程中失败的后果。 这种缺陷可能导致异常的染色质结构。 癌细胞中的异染色质异常是有据可查的1，并且可能代表染色体重排的机制或以其他方式促成肿瘤发生。 1. Dutrillaux，B. Gerbault-Seureau，M.和Zafrani，B.（1990）人类乳腺癌中染色体异常的表征。 30例伴少量染色体改变的类二倍体的比较。 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.