DNMT1 inhibition by pUG-fold quadruplex RNA

Aberrant DNA methylation is one of the earliest hallmarks of cancer. DNMT1 is responsible for methylating newly replicated DNA, but the precise regulation of DNMT1 to ensure faithful DNA methylation remains poorly understood. A link between RNA and chromatin-associated proteins has recently emerged, and several studies have shown that DNMT1 can be regulated by a variety of RNAs. In this study, we have confirmed that human DNMT1 indeed interacts with multiple RNAs, including its own nuclear mRNA. Unexpectedly, we found that DNMT1 exhibits a strong and specific affinity for GU-rich RNAs that form a pUG-fold, a noncanonical G-quadruplex. We find that pUG-fold-capable RNAs inhibit DNMT1 activity by inhibiting binding of hemimethylated DNA, and we additionally provide evidence for multiple RNA binding modes with DNMT1. Together, our data indicate that a human chromatin-associated protein binds to and is regulated by pUG-fold RNA.

Automated summary

Aberrant DNA methylation is an early sign of cancer, and DNMT1 is responsible for methylating newly replicated DNA. In this study, we confirmed that human DNMT1 interacts with multiple RNAs, including its own nuclear mRNA. Surprisingly, DNMT1 showed a strong affinity for GU-rich RNAs that form a noncanonical G-quadruplex structure and can inhibit its activity.