Discovery of synthetic lethal and tumor suppressive paralog pairs in the human genome
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA737515 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14810500.fastq.gz | Fastqsanger.gz | |||
| SRR14810501.fastq.gz | Fastqsanger.gz | |||
| SRR14810502.fastq.gz | Fastqsanger.gz | |||
| SRR14810503.fastq.gz | Fastqsanger.gz | |||
| SRR14810504.fastq.gz | Fastqsanger.gz |
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Project description:CRISPR knockout screens have accelerated the discovery of important cancer genetic dependencies. However, traditional CRISPR-Cas9 screens are limited in their ability to assay the function of redundant or duplicated genes. Paralogs in multi-gene families constitute two-thirds of the protein-coding genome, so this blind spot is the rule, not the exception. To overcome the limitations of single gene CRISPR knockout screens, we developed paired guide RNAs for Paralog gENetic interaction mapping (pgPEN), a pooled CRISPR/Cas9 approach which targets over a thousand duplicated human paralogs in single knockout and double knockout configurations. We applied pgPEN to two cell lineages and discovered that over 10% of human paralogs exhibit synthetic lethality in at least one cellular context. We recovered known synthetic lethal paralogs such as MAP2K1/MAP2K2, important drug targets such as CDK4/CDK6, and numerous other synthetic lethal pairs such as CCNL1/CCNL2. In addition, we identified ten tumor suppressive paralog pairs whose compound loss promotes cell growth. These findings identify a large number of previously unidentified essential gene families and nominate new druggable targets for oncology drug discovery.
2021-08-31 | GSE178179 | GEO
Project description:Abstract Proteins operate within dense interconnected networks, where interactions are necessary both for stabilising proteins and enabling them to execute their molecular functions. Remarkably, the protein-protein interaction networks operating within tumour cells continue to function despite widespread genetic perturbations. Previous work has demonstrated that tumour cells tolerate perturbations of paralogs better than perturbations of singleton genes but the mechanistic means by which paralogs tolerate perturbation remain poorly characterised. Here we systematically profile the proteomic response of tumours and tumour cell lines to gene loss. We find many examples of both active compensation, where deletion of one paralog results in increased abundance of another, and collateral loss, where deletion of one paralog results in reduced abundance of another. Active compensation is enriched among sequence-similar paralog pairs that have high protein-protein interaction degree and that are widely conserved across evolution. Active compensation is also significantly more likely to be observed for gene pairs with a known synthetic lethal relationship. Compensating paralogs have more ubiquitination sites, suggesting a role for post-transcriptional control by protein degradation. Our results support a model whereby loss of one gene results in increased protein abundance of its paralog, stabilising the protein-protein interaction network. Consequently, tumour cells become dependent on the paralog for survival, creating potentially targetable vulnerabilities.
2025-05-07 | PXD055643 | Pride
Project description:CRISPR screens have accelerated the discovery of important cancer vulnerabilities. However, single-gene knockout phenotypes can be masked by redundancy among related genes. Paralogs constitute two-thirds of the human protein-coding genome, so existing methods are likely inadequate for assaying a large portion of gene function. Here, we develop paired guide RNAs for paralog genetic interaction mapping (pgPEN), a pooled CRISPR-Cas9 single- and double-knockout approach targeting more than 2,000 human paralogs. We apply pgPEN to two cell types and discover that 12% of human paralogs exhibit synthetic lethality in at least one context. We recover known synthetic lethal paralogs MEK1/MEK2, important drug targets CDK4/CDK6, and other synthetic lethal pairs including CCNL1/CCNL2. Additionally, we identify ten tumor suppressor paralog pairs whose compound loss promotes cell proliferation. These findings nominate drug targets and suggest that paralog genetic interactions could shape the landscape of positive and negative selection in cancer.
| S-EPMC8534300 | biostudies-literature
Project description:Studying the evolution of binding preferences for 30 paralog TF pairs in S.cerevisiae
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Project description:Paralogs often exhibit functional redundancy, allowing them to effectively compensate for each other's loss. However, this buffering mechanism is frequently disrupted in cancer, exposing unique paralog-specific vulnerabilities. Here, we identify a selective dependency on the splicing factor TRA2A. We find that TRA2A and its paralog TRA2B are synthetic lethal partners that function as widespread and largely redundant activators of both alternative and constitutive splicing. While loss of TRA2A alone is typically neutral due to compensation by TRA2B, we discover that a subset of cancer cell lines are highly TRA2A-dependent. Upon TRA2A depletion, these cell lines exhibit a lack of paralog buffering specifically on shared splicing targets, leading to defects in mitosis and cell death. Notably, TRA2B overexpression rescues both the aberrant splicing and lethality associated with TRA2A loss, indicating that paralog compensation is dosage-sensitive. Together, these findings reveal a complex dosage-dependent relationship between paralogous splicing factors, and highlight how dysfunctional paralog buffering can create a selective dependency in cancer.
2025-04-17 | GSE294883 | GEO
Project description:The FBXW7 tumour suppressor is commonly mutated, deleted or hypermethylated in a variety of cancer histologies. The tumour suppressive role of the FBXW7 protein has been ascribed to its ability to drive the ubiquitination and degradation of oncoproteins via its role as a substrate recognition subunit of SCF complexes that mediate E3 ubiquitin ligation. Despite this molecular understanding, therapeutic approaches that target tumoural FBXW7 defects do not exist. To identify candidate vulnerabilities put in place by FBXW7 dysfunction, we carried out genome-wide CRISPR-Cas9 screens, focussed RNA interference screens and whole proteome mass spectrometry profiling in multiple FBXW7 wild type and defective isogenic cell systems. These identified candidate FBXW7 synthetic lethal effects, including those involving SCF-related proteins (e.g. CAND1), proteins involved in the response to replication fork stress (ATR, RAD9A and CHEK1) and also proteins involved in replication licencing such as CDC7 and its substrate GINS4. The ATR, CHEK1 and CDC7 synthetic lethal effects were confirmed using drug-like small molecule inhibitors. Integration of proteomic profiling data indicated that FBXW7 defective cells express elevated levels of the replication factor RIF1. Functional experiments showed that FBXW7 vs. CDC7 synthetic lethality is RIF1 dependent and explained by RIF1 being required for CDC7 inhibitor-induced replication fork stalling. The delineation of FBXW7 synthetic lethal effects we describe here could serve as the starting point for subsequent drug discovery and/or development in this area.
2024-06-16 | PXD043904 | Pride
Project description:Gene duplication enables the emergence of new functions by lowering the general evolutionary pressure. Previous studies have highlighted the role of specific paralog genes during cell differentiation, e.g., in chromatin remodeling complexes. It remains unexplored whether similar mechanisms extend to other biological functions and whether the regulation of paralog genes is conserved across species. Here, we analyze the expression of paralogs across human tissues, during development and neuronal differentiation in fish, rodents and humans. While ~80% of paralog genes are co-regulated, a subset of paralogs shows divergent expression profiles, contributing to variability of protein complexes. We identify 78 substitutions of paralog eggNOG pairs that occur during neuronal differentiation and are conserved across species. Among these, we highlight a substitution between the paralogs Sec23a and Sec23b subunits of the COPII complex. Altering the ratio between these two genes via silencing-RNA knockdown was able to influence neuronal differentiation in different ways. We propose that remodeling of the vesicular transport system via paralog substitutions is an evolutionary conserved mechanism enabling neuronal differentiation.
2022-03-07 | PXD027195 | Pride
Project description:Gene duplication enables the emergence of new functions by lowering the general evolutionary pressure. Previous studies have highlighted the role of specific paralog genes during cell differentiation, e.g., in chromatin remodeling complexes. It remains unexplored whether similar mechanisms extend to other biological functions and whether the regulation of paralog genes is conserved across species. Here, we analyze the expression of paralogs across human tissues, during development and neuronal differentiation in fish, rodents and humans. While ~80% of paralog genes are co-regulated, a subset of paralogs shows divergent expression profiles, contributing to variability of protein complexes. We identify 78 substitutions of paralog pairs that occur during neuronal differentiation and are conserved across species. Among these, we highlight a substitution between the paralogs Sec23a and Sec23b subunits of the COPII complex. Altering the ratio between these two genes via RNAi-mediated knockdown is sufficient to influence the differentiation of immature neuron. We propose that remodeling of the vesicular transport system via paralog substitutions is an evolutionary conserved mechanism enabling neuronal differentiation.
2022-03-07 | PXD027387 | Pride
Project description:Gene duplication enables the emergence of new functions by lowering the general evolutionary pressure. Previous studies have highlighted the role of specific paralog genes during cell differentiation, e.g., in chromatin remodeling complexes. It remains unexplored whether similar mechanisms extend to other biological functions and whether the regulation of paralog genes is conserved across species. Here, we analyze the expression of paralogs across human tissues, during development and neuronal differentiation in fish, rodents and humans. While ~80% of paralog genes are co-regulated, a subset of paralogs shows divergent expression profiles, contributing to variability of protein complexes. We identify 78 substitutions of paralog eggNOG pairs that occur during neuronal differentiation and are conserved across species. Among these, we highlight a substitution between the paralogs Sec23a and Sec23b subunits of the COPII complex. Altering the ratio between these two genes via silencing-RNA knockdown was able to influence neuronal differentiation in different ways. We propose that remodeling of the vesicular transport system via paralog substitutions is an evolutionary conserved mechanism enabling neuronal differentiation.
2022-03-07 | PXD027191 | Pride