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Modulation of DNMT1 activity by ADP-ribose polymers

Anna Reale1, Giovanna De Matteis, Giada Galleazzi

  • 1Department of Cellular Biotechnologies and Haematology, University of Rome 'La Sapienza', 00161 Rome, Italy.

Oncogene
|January 8, 2005
PubMed

Insights

Poly(ADP-ribose) polymerases (PARP) inhibition leads to DNA hypermethylation. We found that poly ADP-ribose directly binds and inhibits DNA methyltransferase 1 (DNMT1), suggesting a novel regulatory mechanism.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Biochemistry

Background:

  • Competitive inhibition of poly(ADP-ribose) polymerases (PARP) using 3-aminobenzamide in mammalian cells results in genome-wide DNA hypermethylation and anomalous CpG island hypermethylation.
  • The precise molecular mechanisms linking poly(ADP-ribosyl)ation to DNA methylation remain elusive.

Purpose of the Study:

  • To elucidate the molecular connection between poly(ADP-ribosyl)ation and DNA methylation.
  • To investigate the interaction between PARP activity and DNA methyltransferase 1 (DNMT1).

Main Methods:

  • In vitro binding assays to assess the interaction between DNMT1 and poly ADP-ribose polymers.
  • Enzyme activity assays to measure DNMT1 activity upon binding with poly ADP-ribose.
  • Co-immunoprecipitation experiments to determine the in vivo association of PARP1 and DNMT1.

Main Results:

  • DNMT1 non-covalently binds to long and branched ADP-ribose polymers.
  • Binding of poly ADP-ribose to DNMT1 inhibits its DNA methyltransferase activity.
  • PARP1 and DNMT1 form a complex in vivo, where PARP1 is in its ADP-ribosylated isoform.

Conclusions:

  • The interaction between poly ADP-ribose and DNMT1 provides a direct molecular link between PARP activity and DNA methylation.
  • The PARP1-DNMT1 complex, with ADP-ribosylated PARP1, appears to be catalytically inefficient for DNA methylation, suggesting a regulatory role in epigenetic control.

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