ATP-Dependent Chromatin Remodeling
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During transcription, DNA replication and repair, chromatin structure is continually modified to expose specific genetic regions and allow DNA-interacting enzymes access to the DNA. ATP-dependent chromatin remodeling complexes use the energy of ATP hydrolysis to alter chromatin architecture by repositioning, assembling, mobilizing, and restructuring nucleosomes. These complexes are defined by the presence of a conserved SNF2-like, catalytic ATPase subunit that falls into one of four families: SWI/SNF, CHD/Mi-2, ISWI/SNF2L, and INO80. ATP-dependent chromatin remodelers play critical roles in development, cancer, and stem cell biology.
The mammalian switch/sucrose non-fermenting (SWI/SNF) family, also called BAF complexes (Brg/Brm Associated Factor) are thought to regulate gene expression by altering nucleosome positioning and structure. The ATPase subunit in SWI/SNF complexes is either BRM or BRG1; these molecules also contain bromodomains that allow binding to acetylated-lysine residues. BAF complexes exist in a wide variety of cell-specific, and more recently determined, disease-specific heterogenous configurations, each containing a total of 12-14 subunits that always include the core subunits BRM or BRG1, BAF170, BAF155, and BAF47 (also called hSNF5). The configurations change during cell-fate decisions; examples include esBAF in embryonic stem cells, npBAF in neural progenitor cells, and nBAF in postmitotic neurons, each of which contain specific subunit compositions. The genes encoding BAF complex components are mutated in over 20% of human cancers, and have jumped to the forefront of intense anti-cancer efforts.
The chromodomain helicase DNA-binding (CHD) family of ATPases is characterized by a signature chromodomain that elicits binding to methylated lysine residues. The ATPase subunits within this family include CHD1-9. However, CHD3 and 4 are most extensively characterized owing to their role in the the nucleosome remodeling and deacetylase (NuRD) complex. The large, multisubunit NuRD complex contains HDAC1 and 2 proteins and combines ATP-dependent chromatin remodeling with histone deacetylase activities to control both transcriptional activation and repression during embryonic development and cancer.
The imitation switch (ISWI) family controls nucleosome sliding and spacing. The catalytic ATPase in ISWI complexes is either SNF2L or SNF2H, which assemble with 1 to 3 accessory subunits to form 7 unique complexes. Nucleosome remodeling factor (NuRF), the founding member of this family, contains SNF2L and is essential for gene activation during development.
The ATPases within the human INO80 family include INO80, Tip60, and SRCAP, which assemble into large, multisubunit complexes that are responsible for exchanging variant histones into the chromatin structure. Human INO80 assists in the repair of double-strand breaks by evicting nucleosomes, thereby allowing repair factors to access the DNA.
Selected Reviews:
- Bartholomew B. ISWI chromatin remodeling: one primary actor or a coordinated effort?. Curr Opin Struct Biol. 2014;24:150-5.
- Basta J, Rauchman M. The nucleosome remodeling and deacetylase complex in development and disease. Transl Res. 2015;165(1):36-47.
- Hohmann AF, Vakoc CR. A rationale to target the SWI/SNF complex for cancer therapy. Trends Genet. 2014;30(8):356-63.
- Kadoch C, Crabtree GR. Mammalian SWI/SNF chromatin remodeling complexes and cancer: Mechanistic insights gained from human genomics. Sci Adv. 2015;1(5):e1500447.
- Kadoch C, Hargreaves DC, Hodges C, et al. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat Genet. 2013;45(6):592-601.
- Swygert SG, Peterson CL. Chromatin dynamics: interplay between remodeling enzymes and histone modifications. Biochim Biophys Acta. 2014;1839(8):728-36.
- Tosi A, Haas C, Herzog F, et al. Structure and subunit topology of the INO80 chromatin remodeler and its nucleosome complex. Cell. 2013;154(6):1207-19.
We would like to thank Dr. Cigall Kadoch, of the Dana-Farber Cancer Institute and Harvard Medical School, and the Broad Institute of MIT and Harvard for reviewing this diagram.
created February 2018
revised October 2019