RIF1 and PP1 Proteins Play Crucial Role in Resolving DNA Bridges

A new mechanism that ensures correct DNA segregation in cell division, discovered by a research team led by Dr. Gary Ying Wai Chan from the School of Biological Sciences at The University of Hong Kong (HKU), has been published in the journal Cell Reports. The team focused on the roles of RIF1 and protein phosphatase 1 (PP1) in resolving ultrafine DNA bridges formed when sister chromatids are connected by DNA joint molecules during mitosis.

These findings suggest that DNA bridge-binding proteins may serve as potential therapeutic targets for developing anticancer drugs, as DNA bridges are considered a source of genome instability that drives tumorigenesis.

The research team used CRISPR/Cas9 to deplete RIF1 in a cell model during mitosis, discovering that the loss of RIF1 leads to increased DNA damage and micronuclei due to breakage of ultrafine DNA bridges. Additionally, the double-stranded DNA bridges protected by RIF1-PP1 are believed to be resolved by another enzyme known as topoisomerase IIα, which could mediate double-stranded DNA decatenation to ensure proper DNA segregation.

This research not only sheds light on the novel regulatory mechanism by which RIF1-PP1 facilitates the resolution of DNA bridges but also reveals how ultrafine DNA bridges can induce DNA damage and genome instability if left unresolved.

Dr. Gary Chan explains, “The discovery that RIF1 recruits PP1 to the bridges is the first step in understanding how the resolution of ultrafine DNA bridges is regulated by protein phosphorylation/dephosphorylation. The next step is to identify the target substrates of the RIF1-PP1 complex, which can advance our understanding of how different bridge-binding proteins interact with each other and may lead to the identification of new therapeutic targets for cancer.”

The team’s findings on RIF1 and PP1 in resolving ultrafine DNA bridges highlight the importance of understanding the molecular mechanisms that maintain genomic stability during cell division. The research provides insights into the regulatory mechanism of DNA bridge resolution and potential targets for anticancer drug development.

The team aims to identify target substrates of the RIF1-PP1 complex in future studies. In doing so, they hope to advance our understanding of how different bridge-binding proteins interact, as well as identify new therapeutic targets for cancer.