ATR Prohibits Replication Catastrophe by Preventing Global Exhaustion of RPA
Scientists show how cells protect their DNA from catastrophic damage
A research team led by Professor Jiri Lukas from the Novo Nordisk Foundation Center at the University of Copenhagen has unveiled a profound biological process that explains how DNA can be damaged during genome replication. In addition, the scientists developed a new analytical tool to measure the cell’s response to chemotherapy, which could have an important impact on future cancer therapy. The results are now published in the scientific journal Cell.
Cells need to keep their genomic DNA unharmed to stay healthy and the scientists were able to visualize the process of DNA replication and damage directly in cells with an unprecedented detail. They discovered a fundamental mechanism of how proteins protect chromosomes while DNA is being copied (a process called DNA replication), which relies on a protein called RPA. Cells have a limited amount of this protein, which they use as ‘band aids’ to protect the DNA temporarily during replication. If they use up the RPA reservoir, their DNA breaks severely and cells are no longer able to divide.
“We now understand that many drugs used in chemotherapy are toxic against tumours because they make DNA replication difficult and force cancer cells to consume their RPA pool much faster than normal cells usually do. As a result, cancer cells are constantly at the verge of falling into a ‘replication catastrophe’, a condition from which they cannot recover, and which can be used as a powerful means to selectively eliminate cancer cells,” says Luis Ignacio Toledo, the first author of this study.
Contact: Luis Ignacio Toledo 0045 31101966; Jiri Lukas 0045 35325004
Luis Ignacio Toledo1, Matthias Altmeyer1, Maj-Britt Rask1, Claudia Lukas1, Dorthe Helena Larsen1, Lou Klitgaard Povlsen2, Simon Bekker-Jensen2, Niels Mailand2, Jiri Bartek3,4, and Jiri Lukas1*
1Chromosome Stability and Dynamics Group, 2Ubiquitin Signaling Group, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark. 3Genome Integrity Unit, Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100,Copenhagen, Denmark, 4Institute of Molecular and Translational Medicine, Faculty of Medicine, Palacky University, CZ-775 15 Olomouc, Czech Republic