ATP-Dependent Chromatin Remodeling Interactive Signaling Pathway
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.
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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