Abstract
In a process linked to DNA replication, duplicated chromosomes are entrapped in large, circular cohesin complexes and functional sister chromatid cohesion (SCC) is established by acetylation of the SMC3 cohesin subunit. Roberts Syndrome (RBS) and Warsaw Breakage Syndrome (WABS) are rare human developmental syndromes that are characterized by defective SCC. RBS is caused by mutations in the SMC3 acetyltransferase ESCO2, whereas mutations in the DNA helicase DDX11 lead to WABS. We found that WABS-derived cells predominantly rely on ESCO2, not ESCO1, for residual SCC, growth and survival. Reciprocally, RBS-derived cells depend on DDX11 to maintain low levels of SCC. Synthetic lethality between DDX11 and ESCO2 correlated with a prolonged delay in mitosis, and was rescued by knockdown of the cohesin remover WAPL. Rescue experiments using human or mouse cDNAs revealed that DDX11, ESCO1 and ESCO2 act on different but related aspects of SCC establishment. Furthermore, a DNA binding DDX11 mutant failed to correct SCC in WABS cells and DDX11 deficiency reduced replication fork speed. We propose that DDX11, ESCO1 and ESCO2 control different fractions of cohesin that are spatially and mechanistically separated.
Highlights
Sister chromatid cohesion (SCC) is mediated by cohesin, a presumed DNA-entrapping ring formed by structural maintenance of chromosome 1 and 3 (SMC1 and SMC3), RAD21 and SA1/2
During DNA replication, stable cohesion is established in a process involving SMC3 acetylation by ESCO1 and ESCO2, which leads to the recruitment of Sororin and subsequent inhibition of WAPL activity [5,6,7]
Synthetic lethality of DDX11 and ESCO2 is conserved in different human cell lines
Summary
Sister chromatid cohesion (SCC) is mediated by cohesin, a presumed DNA-entrapping ring formed by structural maintenance of chromosome 1 and 3 (SMC1 and SMC3), RAD21 and SA1/2. The loader complex MAU2-NIPBL loads DNA into cohesin rings [1,2,3], whereas it can be released by the cohesin remover WAPL [4]. During DNA replication, stable cohesion is established in a process involving SMC3 acetylation by ESCO1 and ESCO2, which leads to the recruitment of Sororin and subsequent inhibition of WAPL activity [5,6,7]. Prior to chromatid separation in anaphase, cohesin needs to be removed, which happens in two rounds and via two distinct pathways [8, 9].
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