Coordination of DNA Damage Responses via the Smc5/Smc6 Complex

Abstract

The detection of DNA damage activates DNA repair pathways and checkpoints to allow time for repair. Ultimately, these responses must be coordinated to ensure that cell cycle progression is halted until repair is completed. Several multiprotein complexes containing members of the structural maintenance of chromosomes family of proteins have been described, including the condensin and cohesin complexes, that are critical for chromosomal organization. Here we show that the Smc5/Smc6 (Smc5/6) complex is required for a coordinated response to DNA damage and normal chromosome integrity. Fission yeast cells lacking functional Smc6 initiate a normal checkpoint response to DNA damage, culminating in the phosphorylation and activation of the Chk1 protein kinase. Despite this, cells enter a lethal mitosis, presumably without completion of DNA repair. Another subunit of the complex, Nse1, is a conserved member of this complex and is also required for this response. We propose that the failure to maintain a checkpoint response stems from the lack of ongoing DNA repair or from defective chromosomal organization, which is the signal to maintain a checkpoint arrest. The Smc5/6 complex is fundamental to genome integrity and may function with the condensin and cohesin complexes in a coordinated manner.

We are grateful to Alan Lehmann for the provision of anti-Rad18 sera, Mitsuhiro Yanagida for top2 plasmids, Tsukasa Matsunaga for the TDM-2 antibody, and Michael Krien and Doris Germain for critical reading of the manuscript.

S.H. is the recipient of a University of Melbourne Research Scholarship, and M.O. is a Scholar of the Leukemia and Lymphoma Society. This research was also supported by grants from the Australian Research Council (A00103857) and the NIH/NCI (CA100076-01).