Polytene Chromosomes - A Portrait of Functional Organization of the Drosophila Genome.

This mini-review is devoted to the problem genetic meaning of main polytene chromosome structures - bands and interbands. Generally, densely packed chromatin forms black bands, moderately condensed regions form grey loose bands, whereas decondensed regions of the genome appear as interbands. Recent progress in the annotation of the Drosophila genome and epigenome has made it possible to compare the banding pattern and the structural organization of genes, as well as their activity. This was greatly aided by our ability to establish the borders of bands and interbands on the physical map, which allowed to perform comprehensive side-by-side comparisons of cytology, genetic and epigenetic maps and to uncover the association between the morphological structures and the functional domains of the genome. These studies largely conclude that interbands 5'-ends of housekeeping genes that are active across all cell types. Interbands are enriched with proteins involved in transcription and nucleosome remodeling, as well as with active histone modifications. Notably, most of the replication origins map to interband regions. As for grey loose bands adjacent to interbands, they typically host the bodies of house-keeping genes. Thus, the bipartite structure composed of an interband and an adjacent grey band functions as a standalone genetic unit. Finally, black bands harbor tissue-specific genes with narrow temporal and tissue expression profiles. Thus, the uniform and permanent activity of interbands combined with the inactivity of genes in bands forms the basis of the universal banding pattern observed in various Drosophila tissues.

Prospect of reprogramming replication licensing for cancer drug development.

Eukaryotic chromosomal DNA replication is preceded by replication licensing which involves the identification of the origin of replication by origin recognition complex (ORC). The ORC loads pre-replication complexes (pre-RCs) through a series of tightly regulated mechanisms where the ORC interacts with Cdc6 to recruit cdt1-MCM2-7 complexes to the origin of replication. In eukaryotes, adherence to regulatory mechanisms of the replication program is required to ensure that all daughter cells carry the exact copy of genetic material as the parent cell. Failure of which leads to the development of genome instability syndromes like cancer, diabetes, etc. In an event of such occurrence, preventing cells from carrying the defaulted genetic material and passing it to other cells hinges on the regulation of chromosomal DNA replication. Thus, understanding the mechanisms underpinning chromosomal DNA replication and particularly replication licensing can expose druggable enzymes, effector molecules, and secondary messengers that can be targeted for diagnosis and therapeutic purposes. Effectively drugging these molecular markers to reprogram pre-replication events can be used to control the fate of chromosomal DNA replication for the treatment of genome instability disorders and in this case, cancer. This review discusses available knowledge of replication licensing in the contest of molecular drug discovery for the treatment of cancer.