Packaging of genomic DNA into chromatin in eukaryotic cells serves to store and protect the genetic materials. However, this creates an obstacle to accessing to the genetic information. Cells have evolved a large family of chromatin remodelling enzymes that alter the chromatin structure and allow access to the DNA as required.
Chromatin remodelers are ATP-dependent superfamily 2 (SF2) helicases/translocases that are broadly involved in various nuclear processes such as chromatin packaging, gene transcription, and DNA replication and repair. Based on the presence of distinct regulatory domains, chromatin remodeler motors are classified into four major families: Swi2/Snf2, ISWI, CHD, and Ino80. These enzymes exhibit distinct and overlapping activities, including nucleosome sliding, nucleosome eviction, nucleosome spacing, and histone exchange, in which DNA translocation is a common theme. Similarities across subfamilies are due to their two conserved RecA-like ATPase motor domains, whereas differences can be attributed to unique regulatory domains and interaction with different regulatory subunits to assemble distinct complexes.
There is great interest in understanding how these enzymes work. The main challenge to the mechanisms of chromatin remodeling concerns how the remodeler enzymes overcome the extensive histone–DNA interactions to slide the nucleosome. To tease these mechanisms apart, it was necessary to establish how chromatin remodelers interact with the nucleosome. In 2016, we determined the crystal structures of Snf2 and ISWI motor domains. In 2017, we determined the cryoEM structure of the motor domains of Snf2 bound to the nucleosome in the nucleotide-free, apo state, which provided the first glimpse into the motor-nucleosome interaction. In 2019, we then determined the structures of Snf2 and ISWI bound to the nucleosome in the presence of ADP and ADP-BeFx. Together, our findings suggest a fundamental mechanism for the DNA translocation that underlies chromatin remodelling.
1. Xia X#, Liu X#, Li T, Fang, X, Chen Z*. Structure of chromatin remodeller Swi2/Snf2 in the resting state. Nat. Struct. Mol. Biol. 23(8):722-9, 2016
2. Yan L#, Wang L#, Tian Y, Xia X, Chen Z*. Structure and regulation of the chromatin remodeller ISWI. Nature 540(7633):466-469, 2016
3. Liu X#, Li M#, Xia X#, Li X＊, Chen Z*. Mechanism of chromatin remodelling revealed by the Snf2-nucleosome structure Nature 544 (7651):440-445, 2017
4. Li M#, Xia X#, Tian Y#, Jia Q#, Liu X#, Ying L, Li M＊, Li X＊, Chen Z*. Mechanism of DNA translocation underlying chromatin remodeling by Snf2 Nature, 567(7748): 409-413, 2019.
5. Yan L#, Wu H#, Li X, Gao N*, Chen Z* Structures of the ISWI-nucleosome complex reveal a conserved mechanism of chromatin remodeling Nat. Struct. Mol. Biol. 26(4):258-266, 2019
6. Yan L, and Chen Z* A Unifying Mechanism of DNA Translocation Underlying Chromatin Remodeling. Trends Biochem. Sci. 45(3):217-227, 2020 (invited review)