A cell cycle-regulated S1x4em-Dpb11 complex promotes the resolution of DNA repair intermediates linked to stalled replication

• Published in: Genes & development 2014-07, Vol.28 (14), p.1604-1619
• Main Authors: Gritenaite, Dalia, Princz, Lissa N, Szakal, Barnabas, Bantele, Susanne CS, Wendeler, Lina, Schilbach, Sandra, Habermann, Bianca H, Matos, Joao, Lisby, Michael, Branzei, Dana, Pfander, Boris
• Format: Article
• Language: English
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.240515.114

A key function of the cellular DNA damage response is to facilitate the bypass of replication fork-stalling DNA lesions. Template switch reactions allow such a bypass and involve the formation of DNA joint molecules (JMs) between sister chromatids. These JMs need to be resolved before cell division; however, the regulation of this process is only poorly understood. Here, we identify a regulatory mechanism in yeast that critically controls JM resolution by the Mus81-Mms4 endonuclease. Central to this regulation is a conserved complex comprising the scaffold proteins Dpb11 and S1x4 that is under stringent control. Cell cycle-dependent phosphorylation of S1x4 by Cdk1 promotes the Dpb11-S1x4 interaction, while in mitosis, phosphorylation of Mms4 by Polo-like kinase Cdc5 promotes the additional association of Mus81-Mms4 with the complex, thereby promoting JM resolution. Finally, the DNA damage checkpoint counteracts Mus81-Mms4 binding to the Dpb11-S1x4 complex. Thus, Dpb11-S1x4 integrates several cellular inputs and participates in the temporal program for activation of the JM-resolving nuclease Mus81.