POLE3-POLE4 Is a Histone H3-H4 Chaperone that Maintains Chromatin Integrity during DNA Replication

Molecular Cell
Roberto BellelliSimon J Boulton

Abstract

Maintenance of epigenetic integrity relies on coordinated recycling and partitioning of parental histones and deposition of newly synthesized histones during DNA replication. This process depends upon a poorly characterized network of histone chaperones, remodelers, and binding proteins. Here we implicate the POLE3-POLE4 subcomplex of the leading-strand polymerase, Polε, in replication-coupled nucleosome assembly through its ability to selectively bind to histones H3-H4. Using hydrogen/deuterium exchange mass spectrometry and physical mapping, we define minimal domains necessary for interaction between POLE3-POLE4 and histones H3-H4. Biochemical analyses establish that POLE3-POLE4 is a histone chaperone that promotes tetrasome formation and DNA supercoiling in vitro. In cells, POLE3-POLE4 binds both newly synthesized and parental histones, and its depletion hinders helicase unwinding and chromatin PCNA unloading and compromises coordinated parental histone retention and new histone deposition. Collectively, our study reveals that POLE3-POLE4 possesses intrinsic H3-H4 chaperone activity, which facilitates faithful nucleosome dynamics at the replication fork.

Citations

Sep 12, 2019·Open Biology·Nicole HustedtDaniel Durocher
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May 6, 2020·The Journal of Biological Chemistry·Paula A Agudelo GarciaMark R Parthun
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Methods Mentioned

BETA
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gel filtration
size-exclusion chromatography
electrophoresis
fluorescence-activated cell sorting
FACS
gel
acetylation

Software Mentioned

Protein Lynx Global Server
GraphPad
GraphPad Prism7
DynamX
iPOND
Improvision
CellProfiler
Volocity
Consurf

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