High-throughput synthetic rescue for exhaustive characterization of suppressor mutations in human genes
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Cellular and Molecular Life Sciences
REVIEW
High‑throughput synthetic rescue for exhaustive characterization of suppressor mutations in human genes Farah Kobaisi1,2,3 · Nour Fayyad3 · Eric Sulpice1 · Bassam Badran2 · Hussein Fayyad‑Kazan2 · Walid Rachidi3 · Xavier Gidrol1 Received: 3 December 2019 / Revised: 21 March 2020 / Accepted: 30 March 2020 © The Author(s) 2020
Abstract Inherited or acquired mutations can lead to pathological outcomes. However, in a process defined as synthetic rescue, phenotypic outcome created by primary mutation is alleviated by suppressor mutations. An exhaustive characterization of these mutations in humans is extremely valuable to better comprehend why patients carrying the same detrimental mutation exhibit different pathological outcomes or different responses to treatment. Here, we first review all known suppressor mutations’ mechanisms characterized by genetic screens on model species like yeast or flies. However, human suppressor mutations are scarce, despite some being discovered based on orthologue genes. Because of recent advances in high-throughput screening, developing an inventory of human suppressor mutations for pathological processes seems achievable. In addition, we review several screening methods for suppressor mutations in cultured human cells through knock-out, knock-down or random mutagenesis screens on large scale. We provide examples of studies published over the past years that opened new therapeutic avenues, particularly in oncology. Keywords Suppressor mutation · Genetic screening · Cell phenotype · Synthetic rescue
Introduction Genetic information encoded by the DNA should be preserved and faithfully transmitted across generations. This process is essential for determining the genetic composition of a species. Therefore, any mutation can alter the life of the affected species. Mutations range from nonsense, missense or frameshifts. These alterations’ outcomes can change the functionality of encoded proteins or block their translation generating a diseased phenotype [1]. However, mutation is a double-edged sword. First, random mutations are the basis of evolution and organism adaptation to the environment, an aspect not discussed here * Xavier Gidrol [email protected] 1
University of Grenoble Alpes, CEA, INSERM, IRIG-BGE U1038, 38000 Grenoble, France
2
Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Lebanese University, Hadath, Lebanon
3
University of Grenoble Alpes, SYMMES/CIBEST UMR 5819 UGA-CNRS-CEA, IRIG/CEA-Grenoble, Grenoble, France
[2]. Second, deleterious mutations have a counterpart: suppressor mutations. Assuming a primary mutation creates a diseased phenotype, a new mutation(s) can reverse its effect to generate a wild-type or less severe phenotype and, thus, is defined as synthetic rescue [3]. Synthetic lethality, on the contrary, involves cell death arising from the combination of loss of function mutations in at least two genes where the loss of function in any gene individually does not contrib
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