Modulation of human histone chaperone nucleophosmin (NPM1) functions by its interacting partners : implications in chromatin dynamics and transcription

Abstract

The entire genetic information in a eukaryotic cell is stored in DNA over two meters (approximately) in length. It is compacted to nearly one hundred thousandth of the dimension at different levels of folding with an equal mass of proteins and forms a nucleoprotein complex called chromatin (Chakravarthy, et al., 2005; Widom, 1998) (Fig. 1.1). At the first level of organization, nearly two superhelical turns of DNA (147 base pairs) are wrapped around an assembly of eight histone molecules to form the nucleosome core particle (NCP) (Luger, et al., 1997; Luger, 2003). The arrays of nucleosomes are connected by linker DNA of variable length and further compacts in various higher organizational levels (Hansen, 2002). The flexible histone tails, linker histone H1, a variety of non-histone proteins, polyamines and divalent metal ions (Fig. 1.1) are involved in the formation of higher order chromatin structures. The DNA has to be linear and naked for different DNA templated processes such as transcription, replication, DNA repair, and recombination (Fig. 1.2). The fluidity of chromatin is maintained in the interphase nucleus (Gasser, 2002), which can be interconverted from transcriptionally blocked to transcriptionally active states, regulated by reversible modification of histones, of other chromatin associated proteins, and of DNA (reviewed in {Jenuwein and Allis, 2001; Berger, 2002; Urnov, 2002}). Apart from reversible post-translational modifications, DNA accessibility at several levels involve the targeted action of ATP dependent chromatin remodeling factors (reviewed in Flaus and Owen-hughes, 2004), histone chaperones and the introduction of core histone variants. Histone variants are specialized core histones that replace major-type histones mostly via replication-independent assembly pathways. They exhibit specific spatio-temporal patterns, and their unique structural properties contribute to the formation of altered chromatin structures (reviewed in Malik and Henikoff, 2003; and Chakravarthy, et al., 2004).