Controlling nucleases that determine our genetic make-up

Speaker: Joao Matos, Institute of Biochemistry, ETH Zürich
Host: Michael Lisby (Section for Functional Genomics)

Abstract
The life cycle of sexually reproducing eukaryotes depends on two specialized chromosome segregation programs: mitosis and meiosis. Whereas mitosis drives the stable propagation of the genome, meiosis promotes genetic diversity and the formation of haploid gametes, which combine at fertilization to restore the diploid state. Remarkably, both genome stability and genetic diversity/haploidisation depend on the cell’s ability to repair damaged chromosomes using homologous recombination.

To support the repair of DNA lesions, recombinases promote pairing and strand-exchange between a damaged chromosome and a homologous DNA template, leading to the formation of joint molecule (JM) intermediates. JMs can be disengaged at an early stage by anti-recombinogenic pathways or, under circumstances that are currently undefined, mature to form Holliday junctions (HJs). During meiosis, HJ processing leads to the formation of reciprocal inter-homolog exchanges (crossovers), which provide the mechanical basis for reductional chromosome segregation. Throughout most of our life cycle, however, recombination must ensure efficient DNA repair while minimizing genetic exchanges, which is crucial for genome stability and cancer avoidance. To this end, mitotic cells disengage JMs to generate non-crossovers. Extensive research has focused on the genetic delineation and biochemical characterization of the pathways involved in JM processing. Paradoxically, however, a similar set of JM processing enzymes appears to function during mitotic and meiotic DNA repair, implying that cells must be capable or regulating their actions.

I will discuss recent work on the regulation of two structure-selective nucleases involved in JM processing, Mus81-Mms4/EME1 and Yen1/GEN1. Rewiring of their activities is crucial for genome stability during mitotic proliferation and for the generation of genetic diversity/haploidisation during meiosis.

Related papers
A cell cycle-regulated Slx4-Dpb11 complex promotes the resolution of DNA repair intermediates linked to stalled replication. Gritenaite D, Princz LN, Szakal B, Bantele SC, Wendeler L, Schilbach S, Habermann BH, Matos J, Lisby M, Branzei D, Pfander B. Genes Dev. 2014 Jul 15;28(14):1604-19. doi: 10.1101/gad.240515.114.

Holliday junction resolution: regulation in space and time. Matos J, West SC. DNA Repair (Amst). 2014 Jul;19:176-81. doi: 10.1016/j.dnarep.2014.03.013. Epub 2014 Apr 24. Review.

Dual control of Yen1 nuclease activity and cellular localization by Cdk and Cdc14 prevents genome instability. Blanco MG, Matos J, West SC. Mol Cell. 2014 Apr 10;54(1):94-106. doi: 10.1016/j.molcel.2014.02.011. Epub 2014 Mar 13.-7-806.