Scientists reveal how a cancer-linked protein shuts down DNA methylation
Researchers used cryo-electron microscopy to map exactly how TCL1A protein blocks DNA methyltransferases, enzymes that control which genes are switched on or off. The discovery could unlock new approaches to treating lymphomas and developmental disorders where this protein goes haywire, with implications for epigenetic drug development.
Originaltitel: Molecular basis for the inhibition of de novo DNA methylation by TCL1A
DNA methyltransferases DNMT3A/B mediate de novo DNA methylation, essential for embryonic development and cell fate determination. Dysregulation of DNMT3A/B causes developmental defects and tumorigenesis. TCL1A is critical for embryogenesis but promotes lymphomagenesis when deregulated. Previous studies suggested TCL1A binds DNMT3A/B and inhibits their activity, but the mechanism remained unclear. Here, we report the cryo-EM structure of the DNMT3A-TCL1A complex, which comprises a DNMT3A dimer bound by two TCL1A dimers. TCL1A interacts with the catalytic domain of DNMT3A, overlapping with the DNMT3L-binding site, and induces extended conformational rearrangements. The target recognition domain and catalytic loop shift markedly, reducing DNA accessibility, while the catalytic loop occupies the SAM-binding pocket, thereby blocking methyltransferase activity. Supported by biochemical assays and molecular dynamics simulations, we propose a dynamic inhibition mechanism in which TCL1A exploits DNMT3A conformational plasticity to suppress de novo DNA methylation. TCL1A binds DNMT3A/B and inhibits their activity. Here, the authors use cryo-EM to determine the structure of TCL1A bound to DNMT3A, and establish the mechanism through which TCL1A inhibits DNMT3A methylation activity.