A CDK1 phospho-switch reprograms TRAIP to unload replisomes in mitosis
Abstract
Cells entering mitosis with incompletely replicated DNA face catastrophic chromosome segregation failure. During interphase, the replisome-associated E3 ubiquitin ligase TRAIP ubiquitylates barriers in front of the fork to allow replisome progression. In mitosis, TRAIP is reprogrammed from a trans -acting to a cis -acting ligase that can ubiquitylate the replisome itself. This enables the processing of unreplicated DNA by promoting replisome disassembly, fork breakage, and joining of the broken chromosome arms. Here, we describe a mechanism for this reprogramming: the ATPase TTF2 is recruited to the replisome, where its noncatalytic N-terminal domain tethers Cyclin B-CDK1-phosphorylated TRAIP to the leading strand DNA polymerase ε in a geometry that allows replisome ubiquitylation. Thus, a phospho-regulated architectural switch alters replisome organization in mitosis to safeguard genome integrity before chromosome segregation.
Article Details
Journal Info
Science
American Association for the Advancement of Science
Authors (14)
Geylani Can
Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Maksym Shyian
Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Archana Krishnamoorthy
Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Samreen Ahmed
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
Yang Lim
Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Alex Wu
Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
Raphael Pavani
Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Manal S. Zaher
Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
André Nussenzweig
Markus Räschle
Molecular Genetics, Department of Biology, RPTU University Kaiserslautern-Landau, Kaiserslautern, Germany.
Thomas E. Wilson
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
Thomas W. Glover
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
Johannes C. Walter
David Pellman