| 1. |
- Hart, Traver, et al.
(författare)
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High-Resolution CRISPR Screens Reveal Fitness Genes and Genotype-Specific Cancer Liabilities
- 2015
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Ingår i: Cell. - : Elsevier BV. - 0092-8674 .- 1097-4172. ; 163:6
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Tidskriftsartikel (refereegranskat)abstract
- The ability to perturb genes in human cells is crucial for elucidating gene function and holds great potential for finding therapeutic targets for diseases such as cancer. To extend the catalog of human core and context-dependent fitness genes, we have developed a high-complexity second-generation genome-scale CRISPR-Cas9 gRNA library and applied it to fitness screens in five human cell lines. Using an improved Bayesian analytical approach, we consistently discover 5-fold more fitness genes than were previously observed. We present a list of 1,580 human core fitness genes and describe their general properties. Moreover, we demonstrate that context-dependent fitness genes accurately recapitulate pathway-specific genetic vulnerabilities induced by known oncogenes and reveal cell-type-specific dependencies for specific receptor tyrosine kinases, even in oncogenic KRAS backgrounds. Thus, rigorous identification of human cell line fitness genes using a high-complexity CRISPR-Cas9 library affords a high-resolution view of the genetic vulnerabilities of a cell.
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| 2. |
- Mirman, Zachary, et al.
(författare)
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53BP1-RIF1-shieldin counteracts DSB resection through CST- and Polα-dependent fill-in.
- 2018
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Ingår i: Nature. - : Springer. - 0028-0836 .- 1476-4687. ; 560:7716, s. 112-116
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Tidskriftsartikel (refereegranskat)abstract
- In DNA repair, the resection of double-strand breaks dictates the choice between homology-directed repair-which requires a 3' overhang-and classical non-homologous end joining, which can join unresected ends1,2. BRCA1-mutant cancers show minimal resection of double-strand breaks, which renders them deficient in homology-directed repair and sensitive to inhibitors of poly(ADP-ribose) polymerase 1 (PARP1)3-8. When BRCA1 is absent, the resection of double-strand breaks is thought to be prevented by 53BP1, RIF1 and the REV7-SHLD1-SHLD2-SHLD3 (shieldin) complex, and loss of these factors diminishes sensitivity to PARP1 inhibitors4,6-9. Here we address the mechanism by which 53BP1-RIF1-shieldin regulates the generation of recombinogenic 3' overhangs. We report that CTC1-STN1-TEN1 (CST)10, a complex similar to replication protein A that functions as an accessory factor of polymerase-α (Polα)-primase11, is a downstream effector in the 53BP1 pathway. CST interacts with shieldin and localizes with Polα to sites of DNA damage in a 53BP1- and shieldin-dependent manner. As with loss of 53BP1, RIF1 or shieldin, the depletion of CST leads to increased resection. In BRCA1-deficient cells, CST blocks RAD51 loading and promotes the efficacy of PARP1 inhibitors. In addition, Polα inhibition diminishes the effect of PARP1 inhibitors. These data suggest that CST-Polα-mediated fill-in helps to control the repair of double-strand breaks by 53BP1, RIF1 and shieldin.
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| 3. |
- Yvon-Durocher, Gabriel, et al.
(författare)
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Across ecosystem comparisons of size structure: methods, approaches and prospects
- 2011
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Ingår i: OIKOS. - : Nordic Ecological Society. - 0030-1299. ; 120:4, s. 550-563
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Tidskriftsartikel (refereegranskat)abstract
- Understanding how ecological communities are structured and how this may vary between different types of ecosystems is a fundamental question in ecology. We develop a general framework for quantifying size-structure within and among different ecosystem types (e. g. terrestrial, freshwater or marine), via the use of a suite of bivariate relationships between organismal size and properties of individuals, populations, assemblages, pair-wise interactions, and network topology. Each of these relationships can be considered a dimension of size-structure, along which real communities lie on a continuous scale. For example, the strength, slope, or elevation of the body mass-versus-abundance or predator size-versus-prey size relationships may vary systematically among ecosystem types. We draw on examples from the literature and suggest new ways to use allometries for comparing among ecosystem types, which we illustrate by applying them to published data. Finally, we discuss how dimensions of size-structure are interconnected and how we could approach this complex hierarchy systematically. We conclude: (1) there are multiple dimensions of size-structure; (2) communities may be size-structured in some of these dimensions, but not necessarily in others; (3) across-system comparisons via rigorous quantitative statistical methods are possible, and (4) insufficient data are currently available to illuminate thoroughly the full extent and nature of differences in size-structure among ecosystem types.
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