Structure of human DPPA3 bound to the UHRF1 PHD finger reveals its functional and structural differences from mouse DPPA3

Commun Biol. 2024 Jun 19;7(1):746. doi: 10.1038/s42003-024-06434-9.

Abstract

DNA methylation maintenance is essential for cell fate inheritance. In differentiated cells, this involves orchestrated actions of DNMT1 and UHRF1. In mice, the high-affinity binding of DPPA3 to the UHRF1 PHD finger regulates UHRF1 chromatin dissociation and cytosolic localization, which is required for oocyte maturation and early embryo development. However, the human DPPA3 ortholog functions during these stages remain unclear. Here, we report the structural basis for human DPPA3 binding to the UHRF1 PHD finger. The conserved human DPPA3 85VRT87 motif binds to the acidic surface of UHRF1 PHD finger, whereas mouse DPPA3 binding additionally utilizes two unique α-helices. The binding affinity of human DPPA3 for the UHRF1 PHD finger was weaker than that of mouse DPPA3. Consequently, human DPPA3, unlike mouse DPPA3, failed to inhibit UHRF1 chromatin binding and DNA remethylation in Xenopus egg extracts effectively. Our data provide novel insights into the distinct function and structure of human DPPA3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • CCAAT-Enhancer-Binding Proteins* / chemistry
  • CCAAT-Enhancer-Binding Proteins* / genetics
  • CCAAT-Enhancer-Binding Proteins* / metabolism
  • Chromatin / metabolism
  • DNA Methylation
  • Humans
  • Mice
  • PHD Zinc Fingers / genetics
  • Protein Binding
  • Ubiquitin-Protein Ligases* / chemistry
  • Ubiquitin-Protein Ligases* / genetics
  • Ubiquitin-Protein Ligases* / metabolism
  • Xenopus laevis / metabolism

Substances

  • CCAAT-Enhancer-Binding Proteins
  • Chromatin
  • Ubiquitin-Protein Ligases
  • UHRF1 protein, human
  • Uhrf1 protein, mouse
  • DPPA3 protein, human
  • Dppa3 protein, mouse