# Mapping of DDX11 genetic interactions defines sister chromatid cohesion as the major dependency

## TL;DR

This study identifies sister chromatid cohesion as a key dependency in cells lacking DDX11, a DNA helicase linked to genome stability and cancer.

## Contribution

The study provides a comprehensive genetic interaction profile of DDX11 loss and identifies synthetic lethal relationships with STAG2 and HASPIN.

## Key findings

- Loss of DDX11 leads to a strong enrichment of sister chromatid cohesion-related genes.
- Synthetic lethality is confirmed between DDX11 and STAG2, a tumor suppressor frequently mutated in cancer.
- The findings suggest DDX11 could be a therapeutic target in STAG2-mutated tumors.

## Abstract

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 anticancer target, we set out to define a complete genetic interaction profile of DDX11 loss in human cell lines. Screening the human genome with clustered regularly interspaced short palindromic repeats (CRISPR) guide RNA drop out screens in DDX11-wildtype (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 tumor 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 tumors with mutations in STAG2.