title: Evolutionary and functional analysis of the invariant SWIM domain in the conserved Shu2/SWS1 protein family from Saccharomyces cerevisiae to Homo sapiens.
abstract: The Saccharomyces cerevisiae Shu2 protein is an important regulator of Rad51, which promotes homologous recombination (HR). Shu2 functions in the Shu complex with Shu1 and the Rad51 paralogs Csm2 and Psy3. Shu2 belongs to the SWS1 protein family, which is characterized by its SWIM domain (CXC...Xn...CXH), a zinc-binding motif. In humans, SWS1 interacts with the Rad51 paralog SWSAP1. Using genetic and evolutionary analyses, we examined the role of the Shu complex in mitotic and meiotic processes across eukaryotic lineages. We provide evidence that the SWS1 protein family contains orthologous genes in early-branching eukaryote lineages (e.g., Giardia lamblia), as well as in multicellular eukaryotes including Caenorhabditis elegans and Drosophila melanogaster. Using sequence analysis, we expanded the SWIM domain to include an invariant alanine three residues after the terminal CXH motif (CXC…Xn…CXHXXA). We found that the SWIM domain is conserved in all eukaryotic orthologs, and accordingly, in vivo disruption of the invariant residues within the canonical SWIM domain inhibits DNA damage tolerance in yeast and protein-protein interactions in yeast and humans. Furthermore, using evolutionary analyses, we found that yeast and Drosophila Shu2 exhibit strong coevolutionary signatures with meiotic proteins, and in yeast, its disruption leads to decreased meiotic progeny. Together our data indicate that the SWS1 family is an ancient and highly conserved eukaryotic regulator of meiotic and mitotic HR.
authors: University of Pittsburgh Cancer Institute and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213.
authors: Stephen K
authors: SK
authors: Godin
authors: Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213.
authors: Camille
authors: C
authors: Meslin
authors: University of Pittsburgh Cancer Institute and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213.
authors: Faiz
authors: F
authors: Kabbinavar
authors: University of Pittsburgh Cancer Institute and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213.
authors: Dominique S
authors: DS
authors: Bratton-Palmer
authors: University of Pittsburgh Cancer Institute and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213.
authors: Christina
authors: C
authors: Hornack
authors: University of Pittsburgh Cancer Institute and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213.
authors: Michael J
authors: MJ
authors: Mihalevic
authors: University of Pittsburgh Cancer Institute and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213.
authors: Kyle
authors: K
authors: Yoshida
authors: University of Pittsburgh Cancer Institute and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213.
authors: Meghan
authors: M
authors: Sullivan
authors: Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213 karab@pitt.edu nclark@pitt.edu.
authors: Nathan L
authors: http://orcid.org/0000-0003-0006-8374
authors: NL
authors: Clark
authors: University of Pittsburgh Cancer Institute and Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213 karab@pitt.edu nclark@pitt.edu.
authors: Kara A
authors: KA
authors: Bernstein
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D017124:Conserved Sequence; D019143:Evolution, Molecular; D006801:Humans; D008969:Molecular Sequence Data; D005810:Multigene Family; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D029702:Schizosaccharomyces pombe Proteins; C000603871:shu2 protein, S cerevisiae
keywords: DNA repair; Shu complex; budding yeast; evolutionary rate covariation; homologous recombination