Philip Hieter

The cohesin complex has conserved roles in sister chromatid cohesion, DNA replication, genome organization, and the DNA damage response. We heterologously expressed the human cohesin complex in yeast to probe the behaviour of human cohesin. Human cohesin was unable to complement loss of function mutations in yeast cohesin, either as single subunits or as complexes, including in the context of co-expressing up to 12 human cohesin-associated genes. Heterologous expression of human cohesin in yeast expressing wildtype yeast cohesin resulted in dominant cohesion dysregulation and DNA damage sensitivity phenotypes. We used co-immunoprecipitation to demonstrate that human SMC proteins interact with endogenous yeast cohesin rings creating dominant-negative hybrid complexes that disrupt endogenous cohesin biology.

DDX11/Chl1R is a conserved DNA helicase with roles in genome maintenance, DNA replication, and chromatid cohesion. Loss of DDX11 in humans leads to the rare cohesinopathy Warsaw Breakage Syndrome. DDX11 has also been implicated in human cancer where it has been proposed to have an oncogenic role and possibly to constitute a therapeutic target. Given the multiple roles of DDX11 in genome stability and its potential as an anti-cancer target, we set out to define a complete genetic interaction profile of DDX11 loss in human cell lines. Screening the human genome with CRISPR guideRNA drop out screens in DDX11-WT or DDX11-deficient cells revealed a strong enrichment of genes with functions related to sister chromatid cohesion. We confirm synthetic lethal relationships between DDX11 and the tumour suppressor cohesin subunit STAG2, which is frequently mutated in several cancer types and the kinase HASPIN. This screen highlights the importance of cohesion in cells lacking DDX11 and suggests DDX11 may be a therapeutic target for tumours with mutations in STAG2.

To highlight the development of new model systems, assays, and resources designed to illuminate rare disease gene function, the Genetics Society of America has launched a special collection of publications in the GSA journals GENETICS and G3: Genes|Genomes|Genetics. This editorial accompanies 9 papers that describe the development of genetic approaches to study rare disease in 4 well-established model systems—yeast (Saccharomyces cerevisiae), worm (Caenorhabditis elegans), fly (Drosophila), and mouse. In most cases, the assays exploit orthologues of rare disease genes in the model organism of choice and use genome engineering to introduce rare disease variants for subsequent phenotypic analysis.

To highlight the development of new model systems, assays, and resources designed to illuminate rare disease gene function, the Genetics Society of America has launched a special collection of publications in the GSA journals GENETICS and G3: Genes|Genomes|Genetics. This editorial accompanies 9 papers that describe the development of genetic approaches to study rare disease in 4 well-established model systems—yeast (Saccharomyces cerevisiae), worm (Caenorhabditis elegans), fly (Drosophila), and mouse. In most cases, the assays exploit orthologues of rare disease genes in the model organism of choice and use genome engineering to introduce rare disease variants for subsequent phenotypic analysis.