Chromatin remodeling and cancer, Part II: ATP-dependent chromatin remodeling

Abstract

Connections between perturbations that lie outside of our genome, that is, epigenetic alternations, and tumorigenesis have become increasingly apparent. Dynamic chromatin remodeling of the fundamental nucleosomal structure (covered in this review) or the covalent marks residing in the histone proteins that make up this structure (covered previously in part I) underlie many fundamental cellular processes, including transcriptional regulation and DNA-damage repair. Dysregulation of these processes has been linked to cancer development. Mechanisms of chromatin remodeling include dynamic interplay between ATP-dependent complexes, covalent histone modifications, utilization of histone variants and DNA methylation. In part II of this series, we focus on connections between ATP-dependent chromatin-remodeling complexes and oncogenesis and discuss the potential clinical implications of chromatin remodeling and cancer.

Figure 1

Schematic illustration of two major mechanisms of ATP-dependent chromatin remodeling. (a) The first mechanism involves utilization of the energy from ATP hydrolysis to bring about ‘chromatin remodeling’, generally defined as nucleosomal structural changes that involve dissociation of DNA-histone contacts (looping), translocation of the nucleosome along DNA (sliding) or eviction of nucleosomes; these changes create more-open or -exposed chromatin regions with increased DNA accessibility. (b) The second mechanism involves utilization of the energy from ATP hydrolysis to bring about ‘exchange’ of nucleosomal subunits, such as H2A–H2B or H2A variants (H2Avar)–H2B dimers, that can be either unmodified or pre-modified with specific post-translational modifications (shown by question mark, see part I). Structural features harbored in histone variants impart context-dependent biological consequences.

Figure 2

Schematic representation of interaction between ATP-dependent chromatin remodeling and covalent histone modifications during transcriptional regulation and the DNA-repair response. (a) Cross-talk between H3K4 trimethylation and nucleosome remodeling factor (NURF) complex during gene activation. Dynamics of H3K4 trimethylation, a prominent covalent histone modification enriched in active chromatin regions, is maintained by its specific ‘writers’, (e.g. the MLL-family histone methyltransferases) and antagonizing ‘erasers’ (e.g. JARID1-family demethylases). Incorporation of the trimethyl-H3K4 mark into an ‘aromatic cage’ formed by the PHD finger within BPTF, a core subunit of the NURF complex, facilitates stabilization of NURF complexes, which, in turn, carry out nucleosome remodeling, leading to the formation of more-open chromatin strucutures and trasnscriptional activation. (b) Cross-talk between phosphorylation of H2A.X (γ-H2A.X) and INO80 remodeling complexes during the DNA double-strand break (DSB) repair response in yeast. Upon insults, such as ionizing radiation (IR), that lead to the formation of DSBs, spreading of γ-H2AX along the region flanking the DSB is induced via Mec1/Tel1 kinases, which are part of DNA-damage checkpoint mechanisms. Phosphorylation of Ser129 of γ-H2AX recruits INO80 remodeling complexes, which, in turn, initiate nuclesomal remodeling and facilitate DNA accessibility to DNA-repair machinery. Restoration of the chromatin state after repair of a DSB is presumably achieved via desphosphorylation of γ-H2A.X by a phosphatase or by H2A–H2B dimer exchange by an ATP-dependent remodeling complex, although detailed mechanisms remain unclear (see question marks).