'DNA repair nucleases: putting chromosomes through the shredder'

Abstract

To prevent the catastrophic segregation of incompletely replicated chromosomes, eukaryotic cells target stalled replication intermediates for nucleolytic resolution in mitosis. The MUS81 endonuclease plays a pivotal role in this process, but whether and how cells prevent it from cleaving related DNA structures arising during unperturbed S-phase was unclear. In recent work we showed that MUS81 is active throughout the cell cycle, but requires association to the SLX4 scaffold for efficient substrate targeting. To preclude toxic processing of vital replication intermediates, WEE1 kinase restrains CDK1-mediated MUS81-SLX4 assembly during S-phase. Accordingly, WEE1 prevents widespread recruitment of MUS81-SLX4 to S-phase chromosomes and WEE1 inhibition elicits extensive cleavage of replication intermediates, triggering chromosome pulverization. Our work suggests that temporally restricted MUS81-SLX4 association suppresses toxic breakage of replication intermediates, while promoting resolution of under-replicated DNAs that would otherwise impair chromosome segregation.

We have recently published these findings (Duda et al., 2016) but are continuing this project with two complementary research lines. On the one hand, we are investigating the mechanism by which CDK1 promotes MUS81-SLX4 association. On the other hand, we are exploring the phenomenon of chromosome pulverization, which was described more than 40 years ago by Johnson and Rao in pioneering cell-cell fusion experiments. Importantly, this phenomenon has recently regained attention since it has been implicated in chromothripsis. Because of its M-phase-specific ability to process replication intermediates, we are investigating whether MUS81-SLX4 might be the elusive mitotic factor that pulverizes replicating chromosomes in cell-cell fusion experiments. I will discuss our progress in both projects

Bio

João Matos was born and raised in Guimarães, the birthplace of Portugal. After finishing his studies in Biochemistry, in 2003, he joined the laboratory of Wolfgang Zachariae at the MPI-CBG, Dresden. His PhD thesis work focused on the regulation of chromosome segregation during meiosis. He moved to London in 2009, to carry out postdoctoral work with Stephen West, at Clare Hall Laboratories. In the West laboratory João worked on the biochemistry of homologous recombination, with particular emphasis on the regulation of structure-selective endonucleases. In 2014 João moved to Zürich, where he was appointed assistant professor and research group leader at ETH. His current research focuses on the regulation of DNA repair in proliferating cells and during meiosis.

His work has been published in world-class journals like Cell, Mol. Cell, Dev. Cell and Cell Rep. and acknowledged with prestigious accolades like the Otto-Hahn medal (Max Planck), an HFSP fellowship, ERC Starting grant or his recent election to the EMBO Young Investigator Program.

For more info: http://www.bc.biol.ethz.ch/research/matos.html