Journal Article

Non-redundant roles in sister chromatid cohesion of the DNA helicase DDX11 and the SMC3 acetyl transferases ESCO1 and ESCO2

Oostra, Anneke B., Wolthuis, Rob M. F., Faramarz, Atiq, Ghandour, Cherien A., van Schie, Janne J. M., Rooimans, Martin A., Balk, Jesper A., de Lange, Job

2020

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acetylation / Acetyltransferase / Acetyltransferases - genetics / Acetyltransferases - metabolism / Animal experimentation / Animals / Biology and life sciences / Cancer / Carrier Proteins - antagonists & inhibitors / Carrier Proteins - genetics / Carrier Proteins - metabolism / Cell cycle / Cell Cycle Proteins - genetics / Cell Cycle Proteins - metabolism / Cell Line / Cell Line, Transformed / Cell Proliferation / Cell survival / Chromatids - metabolism / Chromatids - ultrastructure / Chromosomal Proteins, Non-Histone - genetics / Chromosomal Proteins, Non-Histone - metabolism / Chromosome Breakage / Chromosome Segregation / Chromosomes / Cohesin / Cohesins / Cohesion / Craniofacial Abnormalities - enzymology / Craniofacial Abnormalities - genetics / Craniofacial Abnormalities - pathology / CRISPR / DEAD-box RNA Helicases - genetics / DEAD-box RNA Helicases - metabolism / Deoxyribonucleic acid / DNA / DNA binding / DNA biosynthesis / DNA helicase / DNA Helicases - genetics / DNA Helicases - metabolism / DNA replication / Ectromelia - enzymology / Ectromelia - genetics / Ectromelia - pathology / Epithelial Cells - enzymology / Epithelial Cells - pathology / Fibroblasts / Fibroblasts - enzymology / Fibroblasts - pathology / Gene Expression / Genetic aspects / Genetics / Humans / Hypertelorism - enzymology / Hypertelorism - genetics / Hypertelorism - pathology / Lethality / Medicine and Health Sciences / Mice / Mitosis / Models, Biological / Mutants / Mutation / Nuclear Proteins - antagonists & inhibitors / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / Physical Sciences / Proto-Oncogene Proteins - antagonists & inhibitors / Proto-Oncogene Proteins - genetics / Proto-Oncogene Proteins - metabolism / Replication / RNA, Small Interfering - genetics / RNA, Small Interfering - metabolism / Transferases / Yeast