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Title: Multivalent Interactions by the Set8 Histone Methyltransferase With Its Nucleosome Substrate

Journal Article · · Journal of Molecular Biology
 [1];  [1];  [1]
  1. Pennsylvania State Univ., University Park, PA (United States)

Set8 is the only mammalian monomethyltransferase responsible for H4K20me1, a methyl mark critical for genomic integrity of eukaryotic cells. We present here a structural model for how Set8 uses multivalent interactions to bind and methylate the nucleosome based on crystallographic and solution studies of the Set8/nucleosome complex. Here, our studies indicate that Set8 employs its i-SET and c-SET domains to engage nucleosomal DNA 1 to 1.5 turns from the nucleosomal dyad and in doing so, it positions the SET domain for catalysis with H4 Lys20. Surprisingly, we find that a basic N-terminal extension to the SET domain plays an even more prominent role in nucleosome binding, possibly by making an arginine anchor interaction with the nucleosome H2A/H2B acidic patch. We further show that proliferating cell nuclear antigen and the nucleosome compete for binding to Set8 through this basic extension, suggesting a mechanism for how nucleosome binding protects Set8 from proliferating cell nuclear antigen-dependent degradation during the cell cycle.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
National Inst. of Health; Cancer Research Foundation
Grant/Contract Number:
GM088236; GM111651; DR-2107-12; DFS-14-15
OSTI ID:
1249237
Journal Information:
Journal of Molecular Biology, Vol. 428, Issue 8; ISSN 0022-2836
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 23 works
Citation information provided by
Web of Science

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Cited By (5)

Progress in the Development of Lysine Methyltransferase SETD8 Inhibitors journal July 2016
The emerging role of lysine methyltransferase SETD8 in human diseases journal September 2016
Asymmetry between the two acidic patches dictates the direction of nucleosome sliding by the ISWI chromatin remodeler journal May 2019
Controlling the supramolecular assembly of nucleosomes asymmetrically modified on H4 journal January 2017
A systematic analysis of nucleosome core particle and nucleosome-nucleosome stacking structure journal January 2018

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