5.8: Nucleosome Remodeling
Nucleosomes are the basic units of chromatin compaction. Each nucleosome consists of the DNA bound tightly around a histone core, which makes the DNA inaccessible to DNA binding proteins such as DNA polymerase and RNA polymerase. Hence, the fundamental problem is to ensure access to DNA when appropriate, despite the compact and protective chromatin structure.
Nucleosome remodeling complex
Eukaryotic cells have specialized enzymes called ATP-dependent nucleosome remodeling enzymes. These enzymes bind to both histone and the wound DNA and can facilitate nucleosome sliding - a process where the DNA is pushed relative to the histone core, or partial or complete histone core replacement, altering the composition of nucleosomes and indirectly affecting the chromatin folding. One of the best-known remodeling complexes is Swi/Snf, originally identified in yeast.
Mechanism of action
Two models are proposed to explain nucleosome sliding - Twist diffusion and Loop/bulge propagation. Both these models suggest that DNA distortion propagates over the surface of the nucleosome.
Twist diffusion model
According to this model, a single base pair is transferred between linked DNA and the DNA wrapped around the histone core. This base change causes nucleosomal DNA to twist or untwist to accommodate the gain/loss of base pairs. The twist defect then propagates around the nucleosome from one DNA segment to the next in a process known as twist-diffusion. In this manner the histone octamer would shift along with the DNA by the size of distortion.
According to this model, DNA from the linker region transiently shifts around the nucleosome, creating a bulge/loop. The loop then travels around the histone, creating or disrupting the histone-DNA interactions. This way, the nucleosome core slides on the DNA strand, exposing regions of DNA for genetic activities.
Given the complexity of chromatin folding, both of the models mentioned above may coexist. However, there are specific questions which both models do not explain, indicating the actual processes may be even more complex. For example, how is processivity achieved during sliding? How does each element of the remodeling complex participate in the process? How do remodelers cooperate with histone chaperones?
The nucleosome remodeling ATPase is involved in several genetic mechanisms, such as developmental gene expression, rapid transcription in response to environmental cues, replication of the genome, surveillance of DNA damage, and repair.
Defects in the nucleosome remodeling complex have a wide range of consequences. During embryonic development, failure of nucleosome remodeling can affect viability, and cause morphological defects. It may also lead to problems in DNA repair, resulting in genome instability and cancer.