Molecular crosstalk between metabolic and DNA replication cycles opens up a new way to comprehend diseases marked by unstable genomes

In a paper published on November 10th in Science magazine, research teams lead by Jiri Lukas and Chunaram Choudhary mechanistically explain a long-standing enigma of how metabolic cycles that generate nucleotides are coordinated with the pace of DNA replication that consumes these nucleotides. The scientists discovered a new signaling pathway that is triggered by fluctuations in nucleotide production. They found that such metabolic fluctuations generate low levels of reactive oxygen species (ROS), which are sensed by PRDX2, a replication fork-associated ROS sensor. They further show that when confronted with ROS, PRDX2 oligomers undergo structural rearrangements to smaller subunits that through direct interaction evict a protein called TIMELESS from the replication fork. Since TIMELESS is a powerful accelerator of DNA synthesis, its removal leads to an instant but reversible slowdown of DNA replication.

In addition to illuminating basic principles of how cells compensate for metabolic fluctuation during cell cycle progression, the authors went ahead to show that ROS-induced, PRDX2-mediated, and TIMELESS-executed fork slowdown is exploited by cancer cells to enable DNA replication under elevated metabolic stress. The latter finding opens new opportunities to screen for drugs that may selectively kill cancer cells by lethally accelerating the speed of genome duplication.

Novo Nordisk Foundation Center for Protein Research

Molecular crosstalk between metabolic and DNA replication cycles opens up a new way to comprehend diseases marked by unstable genomes