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Published December 2005 | Published
Journal Article Open

A Network of Multi-Tasking Proteins at the DNA Replication Fork Preserves Genome Stability


To elucidate the network that maintains high fidelity genome replication, we have introduced two conditional mutant alleles of DNA2, an essential DNA replication gene, into each of the approximately 4,700 viable yeast deletion mutants and determined the fitness of the double mutants. Fifty-six DNA2-interacting genes were identified. Clustering analysis of genomic synthetic lethality profiles of each of 43 of the DNA2-interacting genes defines a network (consisting of 322 genes and 876 interactions) whose topology provides clues as to how replication proteins coordinate regulation and repair to protect genome integrity. The results also shed new light on the functions of the query gene DNA2, which, despite many years of study, remain controversial, especially its proposed role in Okazaki fragment processing and the nature of its in vivo substrates. Because of the multifunctional nature of virtually all proteins at the replication fork, the meaning of any single genetic interaction is inherently ambiguous. The multiplexing nature of the current studies, however, combined with follow-up supporting experiments, reveals most if not all of the unique pathways requiring Dna2p. These include not only Okazaki fragment processing and DNA repair but also chromatin dynamics.

Additional Information

© 2005 Budd et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received: August 3, 2005; Accepted: October 12, 2005; Published: December 2, 2005 Editor: Michael Snyder, Yale University, United States of America A previous version of this article appeared as an Early Online Release on October 12, 2005 (DOI: http://dx.doi.org/10.1371/journal.pgen.0010061.eor). Acknowledgments: This work was supported in part by United States Public Health Service grant GM25508 to JLC and by a National Science and Engineering Research Council of Canada grant, a grant from the Canadian Institutes of Health Research, and funds from Genome Canada, the Ontario Genome Institute, and the Ontario Research and Development Challenge Fund to CB. Competing interests: The authors have declared that no competing interests exist. Author contributions: MEB, AHYT, PP, CB, and JLC conceived and designed the experiments. MEB, AHYT, PP, and XP performed the experiments. MEB, AHYT, PP, CB, and JLC analyzed the data. MEB, CB, and JLC wrote the paper.

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