Related Experiment Video

Updated: Mar 7, 2026

Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
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Molecular basis for the inhibition of de novo DNA methylation by TCL1A

Qingting Liu1, Jinhong Li1, Xiaoxiao Wang2,3

  • 1Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Disease of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University, Chengdu, China.

Nature Communications
|March 5, 2026
PubMed

Insights

TCL1A protein binds DNA methyltransferases DNMT3A/B, inhibiting their de novo DNA methylation activity. This structural and mechanistic insight reveals how TCL1A suppresses methylation, impacting development and cancer.

Area of Science:

  • Epigenetics
  • Structural Biology
  • Molecular Biology

Background:

  • DNA methyltransferases DNMT3A/B are crucial for de novo DNA methylation, regulating embryonic development and cell fate.
  • Dysregulation of DNMT3A/B is linked to developmental disorders and cancer.
  • TCL1A is vital for embryogenesis but implicated in lymphomagenesis when deregulated.

Purpose of the Study:

  • To elucidate the molecular mechanism by which TCL1A inhibits DNMT3A/B activity.
  • To determine the structural basis of the DNMT3A-TCL1A interaction.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) to determine the structure of the DNMT3A-TCL1A complex.
  • Biochemical assays to validate functional interactions.
  • Molecular dynamics simulations to explore dynamic inhibition mechanisms.

Main Results:

  • The cryo-EM structure revealed a DNMT3A dimer bound by two TCL1A dimers.
  • TCL1A binds the catalytic domain of DNMT3A, overlapping the DNMT3L-binding site.
  • TCL1A induces conformational changes that block DNA accessibility and methyltransferase activity.

Conclusions:

  • TCL1A dynamically inhibits DNMT3A/B by exploiting conformational plasticity.
  • This mechanism suppresses de novo DNA methylation, offering insights into developmental regulation and tumorigenesis.

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