Synthetic lethality between the cohesin subunits STAG1 and STAG2 in diverse cancer contexts

Lelij, Petra van der; Lieb, Simone; Jude, Julian; Wutz, Gordana; Santos, Catarina P.; Falkenberg, Katrina J.; Schlattl, Andreas; Ban, Jozef; Schwentner, Raphaela; Hoffmann, Thomas; Kovar, Heinrich; Real, Francisco X.; Waldman, Todd; Pearson, Mark; Kraut, Norbert; Peters, Jan‐Michael; Zuber, Johannes; Petronczki, Mark

doi:10.7554/elife.26980

Cited by 99 publications

(57 citation statements)

References 44 publications

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“…Thus for ~13% of the paralogs with variable essentiality, their essentiality can be associated with lower expression of their most sequence similar paralog, suggesting a potential synthetic lethal relationship. These pairs include many of the synthetic lethal relationships between paralogs previously reported in the literature, including ARID1A/ARID1B [33], SMARCA2/SMARCA4 [34,35], STAG1/STAG2 [36,37], ENO1/ENO2 [38], and RPL22/RPL22L1 [39] ( Fig 5C).…”

Section: Synthetic Lethality With Variably Expressed Genes Contributementioning

confidence: 87%

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Paralog buffering contributes to the variable essentiality of genes in cancer cell lines

Kegel

Ryan

2019

Preprint

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What makes a gene essential for cellular survival? In model organisms, such as budding yeast, systematic gene deletion studies have revealed that paralog genes are less likely to be essential than singleton genes and that this can partially be attributed to the ability of paralogs to buffer each other's loss. However, the essentiality of a gene is not a fixed property and can vary significantly across different genetic backgrounds. It is unclear to what extent paralogs contribute to this variation, as most studies have analyzed genes identified as essential in a single genetic background. Here, using gene essentiality profiles of 558 genetically heterogeneous tumor cell lines, we analyze the contribution of paralogy to variable essentiality. We find that, compared to singleton genes, paralogs are less frequently essential and that this is more evident when considering genes with multiple paralogs or with highly sequence similar paralogs. We determine that paralogs derived from whole genome duplication exhibit more variable essentiality than those derived from small-scale duplications. We estimate that in 13-17% of cases the variable essentiality of paralogs can be attributed to buffering relationships between paralog pairs, as evidenced by synthetic lethality. Paralog pairs derived from whole genome duplication and pairs that function in protein complexes are significantly more likely to display such synthetic lethal relationships. Overall we find that many of the observations made using a single strain of budding yeast can be extended to understand patterns of essentiality in genetically heterogeneous cancer cell lines.

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Section: Synthetic Lethality With Variably Expressed Genes Contributementioning

confidence: 87%

“…Our findings suggest a simple approach to prioritize such paralog pairs by focusing on whole genome duplicates coding for subunits of known protein complexes. Many of the reported cancer synthetic lethalities fall into this category [33][34][35][36][37].…”

Section: Prioritizing Paralog Pairs Most Likely To Exhibit Synthetic mentioning

confidence: 99%

Paralog buffering contributes to the variable essentiality of genes in cancer cell lines

Kegel

Ryan

2019

Preprint

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“…It is well established that SA1 and SA2 have overlapping as well as unique functions (35,73,74). Cohesin SA1 plays a more prominent role than SA2 in the regulation of gene expression (74). One major structural difference between SA1 and SA2 proteins is found in the first 75 amino acids of their N-terminal domains (36).…”

Section: Discussionmentioning

confidence: 99%

Cohesin SA2 is a sequence-independent DNA-binding protein that recognizes DNA replication and repair intermediates

Countryman

Fan

Gorthi

et al. 2018

Journal of Biological Chemistry

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Proper chromosome alignment and segregation during mitosis depend on cohesion between sister chromatids, mediated by the cohesin protein complex, which also plays crucial roles in diverse genome maintenance pathways. Current models attribute DNA binding by cohesin to entrapment of dsDNA by the cohesin ring subunits (SMC1, SMC3, and RAD21 in humans). However, the biophysical properties and activities of the fourth core cohesin subunit SA2 (STAG2) are largely unknown. Here, using single-molecule atomic force and fluorescence microscopy imaging as well as fluorescence anisotropy measurements, we established that SA2 binds to both dsDNA and ssDNA, albeit with a higher binding affinity for ssDNA. We observed that SA2 can switch between the 1D diffusing (search) mode on dsDNA and stable binding (recognition) mode at ssDNA gaps. Although SA2 does not specifically bind to centromeric or telomeric sequences, it does recognize DNA structures often associated with DNA replication and double-strand break repair, such as a double-stranded end, single-stranded overhang, flap, fork, and ssDNA gap. SA2 loss leads to a defect in homologous recombination-mediated DNA double-strand break repair. These results suggest that SA2 functions at intermediate DNA structures during DNA transactions in genome maintenance pathways. These findings have important implications for understanding the function of cohesin in these pathways.

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“…However, we may be able to indirectly target Sp1 in cancer by identifying and exploiting its synthetic lethal dependencies. Several recent studies have identified synthetic lethal interactions during mitosis in other contexts (Oser et al, 2019;van der Lelij et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Transcription factor Sp1 regulates mitotic fidelity through Aurora B kinase-mediated condensin I localization

Flashner

Swift

Sowash

et al. 2020

Preprint

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Mitotic chromosome assembly is essential for faithful chromosome segregation. Despite their salient role directing interphase chromatin organization, little is known about how transcription factors mediate this process during mitosis. Here, we characterize a mitosis-specific role for transcription factor specificity protein 1 (Sp1). Sp1 localizes to mitotic centromeres and auxininduced rapid Sp1 degradation results in chromosome segregation errors and aberrant mitotic progression. These defects are driven by anomalous mitotic chromosome assembly. Sp1 degradation results in chromosome condensation defects through reduced condensin complex I localization. Sp1 also mediates the localization and activation of Aurora B kinase early in mitosis, which is essential for condensin complex I recruitment. Underscoring the clinical significance of our findings, aberrant Sp1 expression correlates with aneuploidy in several human cancers, including kidney renal papillary cell carcinoma, ovarian serous cystadenocarcinoma, mesothelioma, cholangiocarcinoma, and hepatocellular carcinoma. Our results suggest that Sp1 protects genomic integrity during mitosis by promoting chromosome assembly.

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Synthetic lethality between the cohesin subunits STAG1 and STAG2 in diverse cancer contexts

Cited by 99 publications

References 44 publications

Paralog buffering contributes to the variable essentiality of genes in cancer cell lines

Paralog buffering contributes to the variable essentiality of genes in cancer cell lines

Cohesin SA2 is a sequence-independent DNA-binding protein that recognizes DNA replication and repair intermediates

Transcription factor Sp1 regulates mitotic fidelity through Aurora B kinase-mediated condensin I localization

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