Hierarchical Modularity and the Evolution of Genetic Interactomes across Species

Ryan, Colm J.; Roguev, Assen; Patrick, Kristin L.; Xu, Jiewei; Jahari, Harlizawati; Tong, Zongtian; Beltrão, Pedro; Shales, Michael; Qu, Hong; Collins, Sean R.; Kliegman, J.I.; Jiang, Lingli; Kuo, Dwight; Tosti, Elena; Kim, Hyun Soo; Edelmann, Winfried; Keogh, Michael Christopher; Greene, Derek; Tang, Chao; Cunningham, Pádraig; Shokat, Kevan M.; Cagney, Gerard; Svensson, J. Peter; Guthrie, Christine; Espenshade, Peter J.; Ideker, Trey; Krogan, Nevan J.

doi:10.1016/j.molcel.2012.05.028

Cited by 192 publications

(281 citation statements)

References 82 publications

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“…1B) (45). In addition, comparisons of genetic interactions between S. pombe and S. cerevisiae suggested that these four proteins form a complex, and we confirmed this biochemically (40). Collectively, these data demonstrate that Tul1, Dsc2, Dsc3, and Ubx3 are subunits of the Tul1 E3 ligase in S. cerevisiae that is homologous to the S. pombe Dsc E3 ligase.…”

Section: Methodssupporting

confidence: 79%

“…Given that Tul1 ubiquitylates Pep12D to target it to the vacuole (13), DSC2, DSC3, and UBX3 are also likely required for Tul1 E3 ligase activity. Finally, published genetic interaction data indicate that these four genes function in the same pathway (40,45).…”

Section: Discussionmentioning

confidence: 97%

“…We did not identify an S. cerevisiae homolog for dsc4. We named the two uncharacterized genes YOL073C and YOR223W, DSC2 and DSC3, respectively (40). Tul1 is an integral membrane RING E3 ubiquitin ligase that localizes to the Golgi (13).…”

Section: Methodsmentioning

confidence: 99%

“…Tul1 E3 Ligase Consists of Subcomplexes-Dsc2 binds to Tul1, Dsc3, and Ubx3 when purified from detergent cell extracts (40). To confirm that these proteins constitute a single complex and to probe its architecture, we performed coimmunoprecipitation analysis for each subunit and tested the requirement of individual subunits for complex assembly.…”

Section: Methodsmentioning

confidence: 99%

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Identification of Candidate Substrates for the Golgi Tul1 E3 Ligase Using Quantitative diGly Proteomics in Yeast

Tong

Kim

Pandey

et al. 2014

Molecular & Cellular Proteomics

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Maintenance of protein homeostasis is essential for cellular survival. Central to this regulation are mechanisms of protein quality control in which misfolded proteins are recognized and degraded by the ubiquitin-proteasome system. One well-studied protein quality control pathway requires endoplasmic reticulum ( Control of protein homeostasis or proteostasis is key for cell function and survival (1). An important aspect of proteostasis is protein quality control in which misfolded proteins are recognized and degraded by the ubiquitin-proteasome pathway (2). Complex mechanisms regulate whether proteins are targeted for degradation, but ultimately misfolded proteins are recognized and ubiquitylated by specific E2 ubiquitin-conjugating enzymes and E3 ubiquitin ligases (3). One well-studied protein quality control pathway is ER-associated degradation (ERAD) 1 (4 -6). ER luminal and membrane proteins are targeted for cytosolic proteasomal degradation by a set of multisubunit E3 ligases integral to the ER membrane, such as Hrd1 and Doa10 in Saccharomyces cerevisiae and Hrd1 and gp78 in mammals. Key open questions in the protein quality control field are (i) what are the physiological substrates of protein quality control pathways and (ii) how do these E3 ligases recognize proteins for degradation.The sterol regulatory element-binding protein (SREBP) family of transcription factors regulates lipid homeostasis in mammals and fungi (7). These ER membrane-bound proteins are proteolytically activated in the Golgi to release the transcription factor domain from the membrane, allowing it to

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Section: Methodssupporting

confidence: 79%

Section: Discussionmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Identification of Candidate Substrates for the Golgi Tul1 E3 Ligase Using Quantitative diGly Proteomics in Yeast

Tong

Kim

Pandey

et al. 2014

Molecular & Cellular Proteomics

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“…In this regard, we find that disruption of the telomeric association of arm regions in sap1-1 cells lacking Shelterin components correlates with increased accumulation of DNA damage. Moreover, certain Shelterin components show negative genetic interactions with DNA repair and checkpoint factors (44).…”

Section: Discussionmentioning

confidence: 99%

Shelterin components mediate genome reorganization in response to replication stress

Mizuguchi

Taneja

Matsuda

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The dynamic nature of genome organization impacts critical nuclear functions including the regulation of gene expression, replication, and DNA damage repair. Despite significant progress, the mechanisms responsible for reorganization of the genome in response to cellular stress, such as aberrant DNA replication, are poorly understood. Here, we show that fission yeast cells carrying a mutation in the DNA-binding protein Sap1 show defects in DNA replication progression and genome stability and display extensive changes in genome organization. Chromosomal regions such as subtelomeres that show defects in replication progression associate with the nuclear envelope in sap1 mutant cells. Moreover, highresolution, genome-wide chromosome conformation capture (Hi-C) analysis revealed prominent contacts between telomeres and chromosomal arm regions containing replication origins proximal to binding sites for Taz1, a component of the Shelterin telomere protection complex. Strikingly, we find that Shelterin components are required for interactions between Taz1-associated chromosomal arm regions and telomeres. These analyses reveal an unexpected role for Shelterin components in genome reorganization in cells experiencing replication stress, with important implications for understanding the mechanisms governing replication and genome stability.T he 3D organization of the eukaryotic genome creates specialized microenvironments that play important roles in various nuclear processes (1). In addition to regulation of gene expression, proper execution of the DNA replication program and DNA damage repair also involve dynamic organization of the genome (2, 3). Indeed, computational analyses indicate spatial segregation of replication origins based on their timing of firing during S-phase (4), suggesting that besides local chromatin structure, the 3D organization of chromosomes is an important contributing factor in the spatiotemporal control of replication (5, 6). Despite important advances, understanding the connections between diverse chromosomal events and genome organization remains an important challenge.The complexities of genome organization have been studied in several model organisms, including the fission yeast Schizosaccharomyces pombe, for which the 3D organization has been explored at high resolution (7,8). This simple eukaryote contains the basic chromosomal elements of more complex systems, including partitioning of the genome into euchromatin and heterochromatin domains. The S. pombe genome conforms to a Rabl organization pattern in which centromere clusters and telomere clusters are anchored at opposing sides of the nuclear periphery (9, 10). In addition, two key elements shape genome architecture: cohesin-dependent locally crumpled 50-to 100-kb repeating elements called "globules" on chromosome arms and the constraints imposed by the compaction of the chromatin fiber by heterochromatin domains such as at pericentromeric regions (8). The relatively small size of the S. pombe genome combined with the conserved genome...

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Genetic interaction analysis of point mutations enables interrogation of gene function at a residue‐level resolution

et al. 2014

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We have achieved a residue-level resolution of genetic interaction mapping – a technique that measures how the function of one gene is affected by the alteration of a second gene – by analyzing point mutations. Here, we describe how to interpret point mutant genetic interactions, and outline key applications for the approach, including interrogation of protein interaction interfaces and active sites, and examination of post-translational modifications. Genetic interaction analysis has proven effective for characterizing cellular processes; however, to date, systematic high-throughput genetic interaction screens have relied on gene deletions or knockdowns, which limits the resolution of gene function analysis and poses problems for multifunctional genes. Our point mutant approach addresses these issues, and further provides a tool for in vivo structure-function analysis that complements traditional biophysical methods. We also discuss the potential for genetic interaction mapping of point mutations in human cells and its application to personalized medicine.

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Hierarchical Modularity and the Evolution of Genetic Interactomes across Species

Cited by 192 publications

References 82 publications

Identification of Candidate Substrates for the Golgi Tul1 E3 Ligase Using Quantitative diGly Proteomics in Yeast

Identification of Candidate Substrates for the Golgi Tul1 E3 Ligase Using Quantitative diGly Proteomics in Yeast

Shelterin components mediate genome reorganization in response to replication stress

Genetic interaction analysis of point mutations enables interrogation of gene function at a residue‐level resolution

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