Targeting protein–protein interactions in the DNA damage response pathways for cancer chemotherapy

McPherson, Kerry Silva; Korzhnev, Dmitry M.

doi:10.1039/d1cb00101a

Cited by 19 publications

(14 citation statements)

References 341 publications

(794 reference statements)

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“…Replication stress is a phenomenon exacerbated in cancer cells because of the loss of DNA repair genes or the activation of oncogenic pathways [85]. To counteract replication stress, cells are equipped with DNA damage response, an extensive network of signaling pathways accounting for recognition of DNA damage, DNA remodeling and repair, DNA damage bypass during replication, cell cycle control, and cell fate decisions in response to DNA alterations [86]. More than 450 genes are involved in this network.…”

Section: Discussionmentioning

confidence: 99%

The Genetic Makeup of Myeloproliferative Neoplasms: Role of Germline Variants in Defining Disease Risk, Phenotypic Diversity and Outcome

Masselli

Pozzi

Carubbi

et al. 2021

Cells

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Myeloproliferative neoplasms are hematologic malignancies typified by a substantial heritable component. Germline variants may affect the risk of developing a MPN, as documented by GWAS studies on large patient cohorts. In addition, once the MPN occurred, inherited host genetic factors can be responsible for tuning the disease phenotypic presentation, outcome, and response to therapy. This review covered the polymorphisms that have been variably associated to MPNs, discussing them in the functional perspective of the biological pathways involved. Finally, we reviewed host genetic determinants of clonal hematopoiesis, a pre-malignant state that may anticipate overt hematologic neoplasms including MPNs.

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Section: Discussionmentioning

confidence: 99%

The Genetic Makeup of Myeloproliferative Neoplasms: Role of Germline Variants in Defining Disease Risk, Phenotypic Diversity and Outcome

Masselli

Pozzi

Carubbi

et al. 2021

Cells

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“…Several PPIs involved in different types of DNA damage response pathways have been explored for the identification of chemotherapeutic agents inducing synthetic lethality in cells, sensitizing the cells to DNA damaging agents, and modulating cell cycle or apoptotic proteins. 32 Although the INTS3-hSSB1 binding interface has never been studied, the availability of the 3D X-ray crystal structure as the SOSS1 complex opened the opportunity to adapt the structure-based drug design scheme. 33 We explored a structure-based design to screen for inhibitors disrupting the INTS3-hSSB1 binding interface.…”

Section: ■ Discussionmentioning

confidence: 99%

“…Recent developments in medicinal chemistry, biochemistry, molecular biology, and biophysics have enabled the further exploration of PPIs in the modulation of biological functions. Several PPIs involved in different types of DNA damage response pathways have been explored for the identification of chemotherapeutic agents inducing synthetic lethality in cells, sensitizing the cells to DNA damaging agents, and modulating cell cycle or apoptotic proteins . Although the INTS3-hSSB1 binding interface has never been studied, the availability of the 3D X-ray crystal structure as the SOSS1 complex opened the opportunity to adapt the structure-based drug design scheme …”

Section: Discussionmentioning

confidence: 99%

Targeting the hSSB1-INTS3 Interface: A Computational Screening Driven Approach to Identify Potential Modulators

Barbhuiya,

Beard,

Shah

et al. 2024

ACS Omega

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Human single-stranded DNA binding protein 1 (hSSB1) forms a heterotrimeric complex, known as a sensor of single-stranded DNA binding protein 1 (SOSS1), in conjunction with integrator complex subunit 3 (INTS3) and C9ORF80. This sensory protein plays an important role in homologous recombination repair of double-strand breaks in DNA to efficiently recruit other repair proteins at the damaged sites. Previous studies have identified elevated hSSB1-mediated DNA repair activities in various cancers, highlighting its potential as an anticancer target. While prior efforts have focused on inhibiting hSSB1 by targeting its DNA binding domain, this study seeks to explore the inhibition of the hSSB1 function by disrupting its interaction with the key partner protein INTS3 in the SOSS1 complex. The investigative strategy entails a molecular docking-based screening of a specific compound library against the three-dimensional structure of INTS3 at the hSSB1 binding interface. Subsequent assessments involve in vitro analyses of protein−protein interaction (PPI) disruption and cellular effects through co-immunoprecipitation and immunofluorescence assays, respectively. Moreover, the study includes an evaluation of the structural stability of ligands at the INTS3 hot-spot site using molecular dynamics simulations. The results indicate a potential in vitro disruption of the INTS3-hSSB1 interaction by three of the tested compounds obtained from the virtual screening with one impacting the recruitment of hSSB1 and INTS3 to chromatin following DNA damage. To our knowledge, our results identify the first set of drug-like compounds that functionally target INTS3-hSSB1 interaction, and this provides the basis for further biophysical investigations that should help to speed up PPI inhibitor discovery.

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“…Similarly, on-target resistance occurs due to the increased (NER) nucleotide excision repair capacity (ERCC1, ERCC3, ERCC4, ERCC5), increased translesion synthesis (POLH, REV3, REV7), increased homologous recombination ability (BRCA1, BRCA2), mismatch repair deficiency (MLH1, MSH2/3/6), and cisplatin-binding protein (VDAC). Further, damaged DNA is repaired by non-homologous end joining (NHEJ) via XRCC4 and base excision repair (BER) via XRCC1, APEX1 which confers to cisplatin resistance [ 14 , 35 , 36 ]. We predicted the involvement of DNA repair by modulating NER (ERCC1, ERCC4, ERCC5, ERCC2), homologous recombination (RAD51C, BRCA1, XRCC3), NHEJ (PRKDC, XRCC5), and BER (APEX1, XRCC1, OGG1, HMGB1) pathways (Supplementary 2 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of hub genes involved in cisplatin resistance in head and neck cancer

Chaudhary

Khanal

Mateti

et al. 2023

Journal of Genetic Engineering and Biotechnology

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Background Cisplatin resistance is one of the major contributors to the poor survival rate among head and neck cancer (HNC) patients. Focusing on the protein–protein interaction rather than a single protein could provide a better understanding of drug resistance. Thus, this study aimed to identify hub genes in a complex network of cisplatin resistance associated genes in HNC chemotherapy via a series of bioinformatic tools. Methods The genes involved in cisplatin resistance were retrieved from the NCBI gene database using “head and neck cancer” and “cisplatin resistance” as key words. The human genes retrieved were analyzed for their interactions and enriched using the STRING database. The interaction between KEGG pathways and genes was visualized in Cytoscape 3.7.2. Further, the hub gene was identified using the Cytohubba plugin of Cytoscape and validated using UALCAN and Human Protein Atlas database. Validated genes were investigated for the drug–gene interaction using the DGIbd database. Results Out of 137 genes obtained using key words, 133 were associated with cisplatin resistance in the human species. A total of 150 KEGG pathways, 82 cellular components, 123 molecular functions, and 1752 biological processes were modulated on enrichment analysis. Out of 37 hub genes, CCND1, AXL, CDKN2A, TERT, and EXH2 genes were found to have significant (p < 0.05) mRNA expression and effect on overall survival whereas protein expression was found to be positive for all the significant genes except TERT. Thus, they can be targeted with palbociclib, methotrexate, bortezomib and fluorouracil, sorafenib, dasatinib, carboplatin, paclitaxel, gemcitabine, imatinib, doxorubicin, and vorinostat. Conclusion As the pathogenesis of head and neck cancer is complex, targeting hub genes and associated pathways involved in cisplatin resistance could bring a milestone change in the drug discovery and management of drug resistance which might uplift overall survival among HNC patients.

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Targeting protein–protein interactions in the DNA damage response pathways for cancer chemotherapy

Abstract: Cellular DNA damage response (DDR) is an extensive signaling network that orchestrates DNA damage recognition, repair and avoidance, cell cycle progression and cell death. DDR alternation is a hallmark of...

Cited by 19 publications

References 341 publications

The Genetic Makeup of Myeloproliferative Neoplasms: Role of Germline Variants in Defining Disease Risk, Phenotypic Diversity and Outcome

The Genetic Makeup of Myeloproliferative Neoplasms: Role of Germline Variants in Defining Disease Risk, Phenotypic Diversity and Outcome

Targeting the hSSB1-INTS3 Interface: A Computational Screening Driven Approach to Identify Potential Modulators

Identification of hub genes involved in cisplatin resistance in head and neck cancer

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