Alternative splicing and allosteric regulation modulate the chromatin binding of UHRF1.

Maria Tauber, Sarah Kreuz, Alexander Lemak, Papita Mandal, Zhadyra Yerkesh, Alaguraj Veluchamy, Bothayna Al-Gashgari, Abrar Aljahani, Lorena V Cortés-Medina, Dulat Azhibek, Lixin Fan, Michelle S Ong, Shili Duan, Scott Houliston, Cheryl H Arrowsmith, Wolfgang Fischle

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


UHRF1 is an important epigenetic regulator associated with apoptosis and tumour development. It is a multidomain protein that integrates readout of different histone modification states and DNA methylation with enzymatic histone ubiquitylation activity. Emerging evidence indicates that the chromatin-binding and enzymatic modules of UHRF1 do not act in isolation but interplay in a coordinated and regulated manner. Here, we compared two splicing variants (V1, V2) of murine UHRF1 (mUHRF1) with human UHRF1 (hUHRF1). We show that insertion of nine amino acids in a linker region connecting the different TTD and PHD histone modification-binding domains causes distinct H3K9me3-binding behaviour of mUHRF1 V1. Structural analysis suggests that in mUHRF1 V1, in contrast to V2 and hUHRF1, the linker is anchored in a surface groove of the TTD domain, resulting in creation of a coupled TTD-PHD module. This establishes multivalent, synergistic H3-tail binding causing distinct cellular localization and enhanced H3K9me3-nucleosome ubiquitylation activity. In contrast to hUHRF1, H3K9me3-binding of the murine proteins is not allosterically regulated by phosphatidylinositol 5-phosphate that interacts with a separate less-conserved polybasic linker region of the protein. Our results highlight the importance of flexible linkers in regulating multidomain chromatin binding proteins and point to divergent evolution of their regulation.
Original languageEnglish (US)
JournalNucleic acids research
StatePublished - Jul 2 2020

Bibliographical note

KAUST Repository Item: Exported on 2020-10-01
Acknowledgements: We thank Patrick Cramer (MPI-bpc) and Stefan Arold (KAUST) for accessing equipment for FP and MST measurements, Henning Urlaub (MPI-bpc) for MS analyses, KAUST Core Laboratories for MS analyses, help with confocal microscopy and flow cytometry and members of the Fischle laboratory for stimulating discussions.


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