Exploring Proteomic Drug Targets, Therapeutic Strategies and Protein - Protein Interactions in Cancer: Mechanistic View

Dar, Khalid Bashir; Bhat, Aashiq Hussain; Amin, Shajrul; Anjum, Syed; Reshi, Bilal Ahmad; Zargar, Mohammad Afzal; Akbar, Muhammad; Ganie, Showkat Ahmad

doi:10.2174/1568009618666180803104631

Cited by 11 publications

(10 citation statements)

References 116 publications

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“…Consequently, it has been suggested that all cancer cells are likely defective in some aspect of DNA repair (69,70). Protein–protein interactions are essential for most cellular functions, including but not limited to replication, transcription, mitochondrial function, apoptosis and DNA repair (19,71–74). The BER pathway can be represented as a series of coordinated and sequential DNA repair protein complexes.…”

Section: Discussionmentioning

confidence: 99%

Stability and sub-cellular localization of DNA polymerase β is regulated by interactions with NQO1 and XRCC1 in response to oxidative stress

Fang

Andrews

Sharma

et al. 2019

Nucleic Acids Research

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Protein–protein interactions regulate many essential enzymatic processes in the cell. Somatic mutations outside of an enzyme active site can therefore impact cellular function by disruption of critical protein–protein interactions. In our investigation of the cellular impact of the T304I cancer mutation of DNA Polymerase β (Polβ), we find that mutation of this surface threonine residue impacts critical Polβ protein–protein interactions. We show that proteasome-mediated degradation of Polβ is regulated by both ubiquitin-dependent and ubiquitin-independent processes via unique protein–protein interactions. The ubiquitin-independent proteasome pathway regulates the stability of Polβ in the cytosol via interaction between Polβ and NAD(P)H quinone dehydrogenase 1 (NQO1) in an NADH-dependent manner. Conversely, the interaction of Polβ with the scaffold protein X-ray repair cross complementing 1 (XRCC1) plays a role in the localization of Polβ to the nuclear compartment and regulates the stability of Polβ via a ubiquitin-dependent pathway. Further, we find that oxidative stress promotes the dissociation of the Polβ/NQO1 complex, enhancing the interaction of Polβ with XRCC1. Our results reveal that somatic mutations such as T304I in Polβ impact critical protein–protein interactions, altering the stability and sub-cellular localization of Polβ and providing mechanistic insight into how key protein–protein interactions regulate cellular responses to stress.

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Section: Discussionmentioning

confidence: 99%

Stability and sub-cellular localization of DNA polymerase β is regulated by interactions with NQO1 and XRCC1 in response to oxidative stress

Fang

Andrews

Sharma

et al. 2019

Nucleic Acids Research

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“…Examples of biomedically important SLiM‐dependent interaction domains are: kinase (e.g., cancer), phosphatase (e.g., diabetes, cancer, autism), PDZ (e.g., cystic fibrosis, cancer, pain/addiction), SH2 (e.g., immunodeficiency, X‐linked agammaglobulinemia), SH3 (e.g., kidney disease), PTB (e.g., Alzheimer's disease, diabetes, and coronary heart disease), and WW (e.g., X‐linked intellectual disabilities, cancer) domains . Therefore, understanding the basic principles of SLiM‐recognition by protein domains promises to provide powerful insight into drug discovery efforts …”

Section: Introductionmentioning

confidence: 99%

MotifAnalyzer‐PDZ: A computational program to investigate the evolution of PDZ‐binding target specificity

et al. 2019

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Recognition of short linear motifs (SLiMs) or peptides by proteins is an important component of many cellular processes. However, due to limited and degenerate binding motifs, prediction of cellular targets is challenging. In addition, many of these interactions are transient and of relatively low affinity. Here, we focus on one of the largest families of SLiM-binding domains in the human proteome, the PDZ domain. These domains bind the extreme C-terminus of target proteins, and are involved in many signaling and trafficking pathways. To predict endogenous targets of PDZ domains, we developed MotifAnalyzer-PDZ, a program that filters and compares all motif-satisfying sequences in any publicly available proteome. This approach enables us to determine possible PDZ binding targets in humans and other organisms. Using this program, we predicted and biochemically tested novel human PDZ targets by looking for strong sequence conservation in evolution. We also identified three C-terminal sequences in choanoflagellates that bind a choanoflagellate PDZ domain, the Monsiga brevicollis SHANK1 PDZ domain (mbSHANK1), with endogenously-relevant affinities, despite a lack of conservation with the targets of a homologous human PDZ domain, SHANK1. All three are predicted to be signaling proteins, with strong sequence homology to cytosolic and receptor tyrosine kinases. Finally, we analyzed and compared the positional amino acid enrichments in PDZ motifsatisfying sequences from over a dozen organisms. Overall, MotifAnalyzer-PDZ is a versatile program to investigate potential PDZ interactions. This proof-ofconcept work is poised to enable similar types of analyses for other SLiM-binding domains (e.g., MotifAnalyzer-Kinase). MotifAnalyzer-PDZ is available at

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“…In some of the current approaches CRISPR applications have been used in chromatin (Adli 2018 ), and targeted epigenetic regulation, precision of CRISPR to achieve large-scale functional screenings by using guided proteins with thousands of copies of sgRNA in each targeted cell to recognize genes that influence an explicit phenotype in an individual (Lino et al 2018 ). These approaches need several technical and analytical improvements, (Dar et al 2018 ) but once recognized as standard approaches, they could be powerful tools to monitor the functionality of large numbers of genes simultaneously. The specificity and in-depth details of these assays are not in scope of this article however in 2018, Dar et al ( 2018 ) and Adli ( 2018 ) have published their excellent analysis in wide range of CRISPR screening and well documented in their articles.…”

Section: The Rise Of Crispr As the Genome Engineering Applicationmentioning

confidence: 99%

“…These approaches need several technical and analytical improvements, (Dar et al 2018 ) but once recognized as standard approaches, they could be powerful tools to monitor the functionality of large numbers of genes simultaneously. The specificity and in-depth details of these assays are not in scope of this article however in 2018, Dar et al ( 2018 ) and Adli ( 2018 ) have published their excellent analysis in wide range of CRISPR screening and well documented in their articles.…”

Section: The Rise Of Crispr As the Genome Engineering Applicationmentioning

confidence: 99%

“…The CRISPR system has inclusive potential for a variety of applications in epigenetic cancer therapy, in gene regulation of oncogenes in cells, multiscale cancer modeling, proteomics methods for drug discovery and protein–protein interactions (PPI) as therapeutic targets in cancer focused studies (Dar et al 2018 ; Sachdeva et al 2015 ; Martínez et al 2012 ), or chromosomal rearrangements in cancers that involve a single balanced fusion, or in combination with one or more fusions that disrupt this balance (Maresch et al 2016 ). It has been studied in details cancer cells accumulate multiple mutations in genes that, can cause development of cancer cells, progression and distant metastasis (Shi et al 2015 ; Weber et al 2015 ; Sánchez-Rivera and Jacks 2015 ; Khan et al 2016 ).…”

Section: Crispr System and Gene-editing In Cancermentioning

confidence: 99%

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CRISPR: a journey of gene-editing based medicine

Golkar

2020

Genes Genom

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CRISPR (Clustered Regularly Interspaced Short Palindromic Repeat) is one of the hallmark of biological tools, contemplated as a valid and hopeful alternatives to genome editing. Advancements in CRISPR-based technologies have empowered scientists with an editing kit that allows them to employ their knowledge for deleting, replacing and lately “Gene Surgery”, and provides unique control over genes in broad range of species, and presumably in humans. These fast-growing technologies have high strength and flexibility and are becoming an adaptable tool with implementations that are altering organism’s genome and easily used for chromatin manipulation. In addition to the popularity of CRISPR in genome engineering and modern biology, this major tool authorizes breakthrough discoveries and methodological advancements in science. As scientists are developing new types of experiments, some of the applications are raising questions about what CRISPR can enable. The results of evidence-based research strongly suggest that CRISPR is becoming a practical tool for genome-engineering and to create genetically modified eukaryotes, which is needed to establish guidelines on new regulatory concerns for scientific communities.

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Exploring Proteomic Drug Targets, Therapeutic Strategies and Protein - Protein Interactions in Cancer: Mechanistic View

Cited by 11 publications

References 116 publications

Stability and sub-cellular localization of DNA polymerase β is regulated by interactions with NQO1 and XRCC1 in response to oxidative stress

Stability and sub-cellular localization of DNA polymerase β is regulated by interactions with NQO1 and XRCC1 in response to oxidative stress

MotifAnalyzer‐PDZ: A computational program to investigate the evolution of PDZ‐binding target specificity

CRISPR: a journey of gene-editing based medicine

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