Mechanism of histone exchange by INO80 chromatin remodeler
Open Access
- Author:
- Lin, Sirong
- Graduate Program:
- Chemistry
- Degree:
- Master of Science
- Document Type:
- Master Thesis
- Date of Defense:
- May 23, 2019
- Committee Members:
- Tae-Hee Lee, Thesis Advisor/Co-Advisor
Joseph Alfred Cotruvo Jr., Committee Member
Xin Zhang, Committee Member - Keywords:
- histone
INO80
chromatin
remodeler
FRET
nucleosome - Abstract:
- The nucleosome, made of an octameric histone protein core wrapped around by ~147 base-pair double-stranded DNA, is the fundamental gene-packing unit in eukaryotes. The structure of the nucleosome is flexible, which is the physical basis of dynamic gene regulation mechanisms. Various biochemical signals are involved in regulating the positions of nucleosomes or altering the composition of histone cores, which are often mediated by chromatin remodelers. A chromatin remodeler INO80 slides nucleosomes and exchanges histone H2A.Z with H2A, which have been associated with transcription activation and active transcription. H2A.Z is enriched in the promoter proximal nucleosomes that can potentially act as physical barriers to help maintain genome integrity. The barriers would be lowered when H2A.Z is replaced with H2A, which would subsequently catalyze gene activation. One of the prevailing hypotheses has been that INO80 carries out this function although its molecular mechanism remains nearly completely unknown. Here I present the mechanism of how INO80 exchanges H2A.Z with H2A based on three-color single-molecule FRET measurements. According to the mechanism, INO80 carries a histone H2A-H2B dimer, unwraps DNA while it translocates along the nucleosome, and exchanges H2A.Z-H2B with H2A-H2B. I also propose that the substrate specificity of the dimer exchange reaction is due to potential preferential binding of INO80 to H2A.Z-H2B over H2A-H2B.