Gene Regulation by Metabolic Enzyme GMP Synthetase and Chromatin Remodeler NuRD

Spatial and temporal control of the gene expression is crucial for normal growth and development of an organism. Environmental stress factors pose a constant threat to normal development of an organism by causing altered gene expression. Cells have evolved counteractive mechanisms to overcome the stress caused by external factors. Among these, stabilization of p53 is the major stress responsive pathway. In response to diverse cellular insults including DNA damage, p53 gets stabilized and regulates the expression of genes that induce cell cycle arrest, senescence, and apoptosis. However, it is unclear how p53 is stabilized upon cellular stress. Chapter 2 describes the identification of nucleotide biosynthetic enzyme GMPS and E3 ubiquitin-ligase TRIM21, as key players in regulation of p53 stability. Upon cellular stress, GMPS stabilizes p53 through USP7-mediated deubiquitylation. GMPS acts as a sensor of the nucleotide pool in the cell and activates p53-mediated replicative stress response to the nucleotides depletion. Thus, GMPS ensures the error free cell divisions by coordinating nucleotide synthesis and p53-mediated cell cycle regulation. TRIM21 negatively regulates p53 stability and function by targeting GMPS to cytoplasm. Since loss of p53 function is reported in more than 50% of human cancers targeting TRIM21 might serve as a therapeutic opportunity for cancer treatment

Remodelers organize cellular chromatin by counteracting intrinsic histone-DNA sequence preferences in a class-specific manner

The nucleosome is the fundamental repeating unit of eukaryotic chromatin. Here, we assessed the interplay between DNA sequence and ATP-dependent chromatin-remodeling factors (remodelers) in the nucleosomal organization of a eukaryotic genome. We compared the genome-wide distribution of Drosophila NURD, (P)BAP, INO80, and ISWI, representing the four major remodeler families. Each remodeler has a unique set of genomic targets and generates distinct chromatin signatures. Remodeler loci have characteristic DNA sequence features, predicted to influence nucleosome formation. Strikingly, remodelers counteract DNA sequence-driven nucleosome distribution in two distinct ways. NURD, (P)BAP, and INO80 increase histone density at their target sequences, which intrinsically disfavor positioned nucleosome formation. In contrast, ISWI promotes open chromatin at sites that are propitious for precise nucleosome placement. Remodelers influe