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Metazoan Scc4 homologs link sister chromatid cohesion to cell and axon migration guidance

Lookup NU author(s): Dr Vlad Seitan, Dr Andrew Banks, Dr Steven Laval, Dr Sarah Newbury, Professor Tom Strachan

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Abstract

Saccharomyces cerevisiae Scc2 binds Scc4 to form an essential complex that loads cohesin onto chromosomes. The prevalence of Scc2 orthologs in eukaryotes emphasizes a conserved role in regulating sister chromatid cohesion, but homologs of Scc4 have not hitherto been identified outside certain fungi. Some metazoan orthologs of Scc2 were initially identified as developmental gene regulators, such as Drosophila Nipped-B, a regulator of cut and Ultrabithorax, and delangin, a protein mutant in Cornelia de Lange syndrome. We show that delangin and Nipped-B bind previously unstudied human and fly orthologs of Caenorhabditis elegans MAU-2, a non-axis-specific guidance factor for migrating cells and axons. PSI-BLAST shows that Scc4 is evolutionarily related to metazoan MAU-2 sequences, with the greatest homology evident in a short N-terminal domain, and protein-protein interaction studies map the site of interaction between delangin and human MAU-2 to the N-terminal regions of both proteins. Short interfering RNA knockdown of human MAU-2 in HeLa cells resulted in precocious sister chromatid separation and in impaired loading of cohesin onto chromatin, indicating that it is functionally related to Scc4, and RNAi analyses show that MAU-2 regulates chromosome segregation in C. elegans embryos. Using antisense morpholino oligonucleotides to knock down Xenopus tropicalis delangin or MAU-2 in early embryos produced similar patterns of retarded growth and developmental defects. Our data show that sister chromatid cohesion in metazoans involves the formation of a complex similar to the Scc2-Scc4 interaction in the budding yeast. The very high degree of sequence conservation between Scc4 homologs in complex metazoans is consistent with increased selection pressure to conserve additional essential functions, such as regulation of cell and axon migration during development. © 2006 Seitan et al.


Publication metadata

Author(s): Seitan VC, Banks P, Laval S, Majid NA, Dorsett D, Rana A, Smith J, Bateman A, Krpic S, Hostert A, Rollins RA, Erdjument-Bromage H, Tempst P, Benard CY, Hekimi S, Newbury SF, Strachan T

Publication type: Article

Publication status: Published

Journal: PLoS Biology

Year: 2006

Volume: 4

Issue: 8

Pages: 1411-1425

ISSN (print): 1544-9173

ISSN (electronic): 1545-7885

Publisher: Public Library of Science

URL: http://dx.doi.org/10.1371/journal.pbio.0040242

DOI: 10.1371/journal.pbio.0040242


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Funding

Funder referenceFunder name
Wellcome Trust
087656Wellcome Trust
BB/C005163/1Biotechnology and Biological Sciences Research Council
R01 GM063403NIGMS NIH HHS
R01 GM063403-01NIGMS NIH HHS
R01 GM063403-02NIGMS NIH HHS
R01 GM063403-03NIGMS NIH HHS
R01 GM055683NIGMS NIH HHS

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