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Lookup NU author(s): Yuan Xue, Dr Michael Rushton, Dr Laura MaringeleORCiD
Cells accumulate single-stranded DNA (ssDNA) when telomere capping, DNA replication, or DNA repair is impeded. This accumulation leads to cell cycle arrest through activating the DNA-damage checkpoints involved in cancer protection. Hence, ssDNA accumulation could be an anti-cancer mechanism. However, ssDNA has to accumulate above a certain threshold to activate checkpoints. What determines this checkpoint-activation threshold is an important, yet unanswered question. Here we identify Rif1 (Rap1-Interacting Factor 1) as a threshold-setter. Following telomere uncapping, we show that budding yeast Rif1 has unprecedented effects for a protein, inhibiting the recruitment of checkpoint proteins and RPA (Replication Protein A) to damaged chromosome regions, without significantly affecting the accumulation of ssDNA at those regions. Using chromatin immuno-precipitation, we provide evidence that Rif1 acts as a molecular "band-aid" for ssDNA lesions, associating with DNA damage independently of Rap1. In consequence, small or incipient lesions are protected from RPA and checkpoint proteins. When longer stretches of ssDNA are generated, they extend beyond the junction-proximal Rif1-protected regions. In consequence, the damage is detected and checkpoint signals are fired, resulting in cell cycle arrest. However, increased Rif1 expression raises the checkpoint-activation threshold to the point it simulates a checkpoint knockout and can also terminate a checkpoint arrest, despite persistent telomere deficiency. Our work has important implications for understanding the checkpoint and RPA-dependent DNA-damage responses in eukaryotic cells.
Author(s): Xue Y, Rushton MD, Maringele L
Publication type: Article
Publication status: Published
Journal: PLoS Genetics
Year: 2011
Volume: 7
Issue: 12
Print publication date: 15/12/2011
Date deposited: 02/03/2012
ISSN (electronic): 1553-7390
Publisher: Public Library of Science
URL: http://dx.doi.org/10.1371/journal.pgen.1002417
DOI: 10.1371/journal.pgen.1002417
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