scholarly journals CladeOScope: functional interactions through the prism of clade-wise co-evolution

2021 ◽  
Vol 3 (2) ◽  
Author(s):  
Tomer Tsaban ◽  
Doron Stupp ◽  
Dana Sherill-Rofe ◽  
Idit Bloch ◽  
Elad Sharon ◽  
...  
Keyword(s):  
Web Server ◽  
Function Prediction ◽  
Tree Of Life ◽  
End Joining ◽  
Functional Interactions ◽  
Evolution Analysis ◽  
Powerful Approach ◽  
Non Homologous End Joining ◽  
Phylogenetic Profiling ◽  
Eukaryotic Genomes

Abstract Mapping co-evolved genes via phylogenetic profiling (PP) is a powerful approach to uncover functional interactions between genes and to associate them with pathways. Despite many successful endeavors, the understanding of co-evolutionary signals in eukaryotes remains partial. Our hypothesis is that ‘Clades’, branches of the tree of life (e.g. primates and mammals), encompass signals that cannot be detected by PP using all eukaryotes. As such, integrating information from different clades should reveal local co-evolution signals and improve function prediction. Accordingly, we analyzed 1028 genomes in 66 clades and demonstrated that the co-evolutionary signal was scattered across clades. We showed that functionally related genes are frequently co-evolved in only parts of the eukaryotic tree and that clades are complementary in detecting functional interactions within pathways. We examined the non-homologous end joining pathway and the UFM1 ubiquitin-like protein pathway and showed that both demonstrated distinguished co-evolution patterns in specific clades. Our research offers a different way to look at co-evolution across eukaryotes and points to the importance of modular co-evolution analysis. We developed the ‘CladeOScope’ PP method to integrate information from 16 clades across over 1000 eukaryotic genomes and is accessible via an easy to use web server at http://cladeoscope.cs.huji.ac.il.

Optimization of co-evolution analysis through phylogenetic profiling reveals pathway-specific signals

2020 ◽  
Vol 36 (14) ◽  
pp. 4116-4125 ◽  
Author(s):  
Idit Bloch ◽  
Dana Sherill-Rofe ◽  
Doron Stupp ◽  
Irene Unterman ◽  
Hodaya Beer ◽  
...  
Keyword(s):  
Supplementary Information ◽  
Functional Interaction ◽  
Evolutionary Patterns ◽  
Interaction Prediction ◽  
Functional Interactions ◽  
Evolution Analysis ◽  
Pathway Evolution ◽  
Major Interest ◽  
Phylogenetic Profiling ◽  
The Right

Abstract Summary The exponential growth in available genomic data is expected to reach full sequencing of a million genomes in the coming decade. Improving and developing methods to analyze these genomes and to reveal their utility is of major interest in a wide variety of fields, such as comparative and functional genomics, evolution and bioinformatics. Phylogenetic profiling is an established method for predicting functional interactions between proteins based on similarities in their evolutionary patterns across species. Proteins that function together (i.e. generate complexes, interact in the same pathways or improve adaptation to environmental niches) tend to show coordinated evolution across the tree of life. The normalized phylogenetic profiling (NPP) method takes into account minute changes in proteins across species to identify protein co-evolution. Despite the success of this method, it is still not clear what set of parameters is required for optimal use of co-evolution in predicting functional interactions. Moreover, it is not clear if pathway evolution or function should direct parameter choice. Here, we create a reliable and usable NPP construction pipeline. We explore the effect of parameter selection on functional interaction prediction using NPP from 1028 genomes, both separately and in various value combinations. We identify several parameter sets that optimize performance for pathways with certain biological annotation. This work reveals the importance of choosing the right parameters for optimized function prediction based on a biological context. Availability and implementation Source code and documentation are available on GitHub: https://github.com/iditam/CompareNPPs. Contact [email protected] Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Withanolide D Enhances Radiosensitivity of Human Cancer Cells by Inhibiting DNA Damage Non-homologous End Joining Repair Pathway

2020 ◽  
Vol 9 ◽  
Author(s):  
Jerome Lacombe ◽  
Titouan Cretignier ◽  
Laetitia Meli ◽  
E. M. Kithsiri Wijeratne ◽  
Jean-Luc Veuthey ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cancer Cells ◽  
Human Cancer ◽  
Repair Pathway ◽  
End Joining ◽  
Human Cancer Cells ◽  
Non Homologous End Joining

scholarly journals Regulatory and Functional Involvement of Long Non-Coding RNAs in DNA Double-Strand Break Repair Mechanisms

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1506
Author(s):  
Angelos Papaspyropoulos ◽  
Nefeli Lagopati ◽  
Ioanna Mourkioti ◽  
Andriani Angelopoulou ◽  
Spyridon Kyriazis ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Strand Break ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Dsb Repair ◽  
Repair Mechanisms ◽  
Non Coding Rnas ◽  
Repair Pathways ◽  
Non Homologous End Joining ◽  
Living Organisms

Protection of genome integrity is vital for all living organisms, particularly when DNA double-strand breaks (DSBs) occur. Eukaryotes have developed two main pathways, namely Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR), to repair DSBs. While most of the current research is focused on the role of key protein players in the functional regulation of DSB repair pathways, accumulating evidence has uncovered a novel class of regulating factors termed non-coding RNAs. Non-coding RNAs have been found to hold a pivotal role in the activation of DSB repair mechanisms, thereby safeguarding genomic stability. In particular, long non-coding RNAs (lncRNAs) have begun to emerge as new players with vast therapeutic potential. This review summarizes important advances in the field of lncRNAs, including characterization of recently identified lncRNAs, and their implication in DSB repair pathways in the context of tumorigenesis.

scholarly journals Structural basis for proficient oxidized ribonucleotide insertion in double strand break repair

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Joonas A. Jamsen ◽  
Akira Sassa ◽  
Lalith Perera ◽  
David D. Shock ◽  
William A. Beard ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Time Lapse ◽  
Strand Break ◽  
Structural Basis ◽  
End Joining ◽  
Strand Breaks ◽  
Nucleotide Pools ◽  
Nucleotide Insertion ◽  
Non Homologous End Joining

AbstractReactive oxygen species (ROS) oxidize cellular nucleotide pools and cause double strand breaks (DSBs). Non-homologous end-joining (NHEJ) attaches broken chromosomal ends together in mammalian cells. Ribonucleotide insertion by DNA polymerase (pol) μ prepares breaks for end-joining and this is required for successful NHEJ in vivo. We previously showed that pol μ lacks discrimination against oxidized dGTP (8-oxo-dGTP), that can lead to mutagenesis, cancer, aging and human disease. Here we reveal the structural basis for proficient oxidized ribonucleotide (8-oxo-rGTP) incorporation during DSB repair by pol μ. Time-lapse crystallography snapshots of structural intermediates during nucleotide insertion along with computational simulations reveal substrate, metal and side chain dynamics, that allow oxidized ribonucleotides to escape polymerase discrimination checkpoints. Abundant nucleotide pools, combined with inefficient sanitization and repair, implicate pol μ mediated oxidized ribonucleotide insertion as an emerging source of widespread persistent mutagenesis and genomic instability.

scholarly journals Gene targeting facilitated by engineered sequence-specific nucleases and its potential for applications in crop improvement

2021 ◽  
Author(s):  
Daisuke Miki ◽  
Rui Wang ◽  
Jing Li ◽  
Dali Kong ◽  
Lei Zhang ◽  
...  
Keyword(s):  
Gene Targeting ◽  
Agronomic Traits ◽  
Higher Plants ◽  
Crop Improvement ◽  
Strand Break ◽  
End Joining ◽  
Homology Directed Repair ◽  
Target Dna ◽  
Targeted Gene Editing ◽  
Non Homologous End Joining

Abstract Humans are currently facing the problem of how to ensure that there is enough food to feed all of the world’s population. Ensuring that the food supply is sufficient will likely require the modification of crop genomes to improve their agronomic traits. The development of engineered sequence-specific nucleases (SSNs) paved the way for targeted gene editing in organisms, including plants. SSNs generate a double-strand break (DSB) at the target DNA site in a sequence-specific manner. These DSBs are predominantly repaired via error-prone non-homologous end joining (NHEJ), and are only rarely repaired via error-free homology-directed repair (HDR) if an appropriate donor template is provided. Gene targeting (GT), i.e., the integration or replacement of a particular sequence, can be achieved with combinations of SSNs and repair donor templates. Although its efficiency is extremely low, GT has been achieved in some higher plants. Here, we provide an overview of SSN-facilitated GT in higher plants and discuss the potential of GT as a powerful tool for generating crop plants with desirable features.

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