Mapping the Human Kinome in Response to DNA Damage

Owusu, Michel; Bannauer, Peter; Silva, Joana Ferreira da; Mourikis, Thanos P.; Jones, A G; Marynen, Peter; Caldera, Michael; Wiedner, Marc; Lardeau, Charles-Hugues; Mueller, André C.; Menche, Jörg; Kubicek, Stefan; Ciccarelli, Francesca D.; Loizou, Joanna I.

doi:10.1016/j.celrep.2018.12.087

Cited by 24 publications

(14 citation statements)

References 59 publications

(51 reference statements)

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“…Regarding the checkpoint activity of MARK3, Owusu et al recently reported that the depletion of MARK3 in HAP1 cells increased the genotoxic effects of DNA damaging agents 50 . Although the researchers only focused on the DNA damage response and did not evaluate the metabolic stress response, the study still offers valuable information supporting the possibility of MARK3 being a stress-activated checkpoint kinase.…”

Section: Discussionmentioning

confidence: 99%

The metabolic stress-activated checkpoint LKB1-MARK3 axis acts as a tumor suppressor in high-grade serous ovarian carcinoma

Machino

Kaneko²,

Komatsu

et al. 2022

Commun Biol

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High-grade serous ovarian carcinoma (HGSOC) is the most aggressive gynecological malignancy, resulting in approximately 70% of ovarian cancer deaths. However, it is still unclear how genetic dysregulations and biological processes generate the malignant subtype of HGSOC. Here we show that expression levels of microtubule affinity-regulating kinase 3 (MARK3) are downregulated in HGSOC, and that its downregulation significantly correlates with poor prognosis in HGSOC patients. MARK3 overexpression suppresses cell proliferation and angiogenesis of ovarian cancer cells. The LKB1-MARK3 axis is activated by metabolic stress, which leads to the phosphorylation of CDC25B and CDC25C, followed by induction of G2/M phase arrest. RNA-seq and ATAC-seq analyses indicate that MARK3 attenuates cell cycle progression and angiogenesis partly through downregulation of AP-1 and Hippo signaling target genes. The synthetic lethal therapy using metabolic stress inducers may be a promising therapeutic choice to treat the LKB1-MARK3 axis-dysregulated HGSOCs.

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Section: Discussionmentioning

confidence: 99%

The metabolic stress-activated checkpoint LKB1-MARK3 axis acts as a tumor suppressor in high-grade serous ovarian carcinoma

Machino

Kaneko²,

Komatsu

et al. 2022

Commun Biol

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“…While scalable, sensitive protein fusion screening remains challenging, high-throughput oligonucleotide library synthesis enables screening of highly diverse peptide fusion constructs. Reasoning that peptides derived from DNA repair-related proteins may encode domains capable of altering prime editing efficiency, we designed a library of 85-amino acid peptides comprising complete 2X tiling of 417 DNA repair-related proteins 9 , 10 and 29 housekeeping genes as controls (Supplementary Data 1 ). We also included 5458 DNA repair-related mutant peptides with all possible S– > E and T– > E phosphomimetic substitutions.…”

Section: Resultsmentioning

confidence: 99%

Peptide fusion improves prime editing efficiency

et al. 2022

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Prime editing enables search-and-replace genome editing but is limited by low editing efficiency. We present a high-throughput approach, the Peptide Self-Editing sequencing assay (PepSEq), to measure how fusion of 12,000 85-amino acid peptides influences prime editing efficiency. We show that peptide fusion can enhance prime editing, prime-enhancing peptides combine productively, and a top dual peptide-prime editor increases prime editing significantly in multiple cell lines across dozens of target sites. Top prime-enhancing peptides function by increasing translation efficiency and serve as broadly useful tools to improve prime editing efficiency.

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“…Carmustine is another alkylating agent commonly used in cancers related to the nervous system. Carmustine causes both intrastrand and interstrand crosslinks and has also been reported to be synthetic lethal with cells lacking kinases such as MARK3 (Owusu et al, 2019). The activities of many alkylating agents are correlated with the gene Schlafen-11 (SLFN-11), a putative component of DNA damage response that induces cell cycle arrest and apoptosis upon DNA damage (Zoppoli et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Artificial intelligence platform, RADR®, aids in the discovery of DNA damaging agent for the ultra-rare cancer Atypical Teratoid Rhabdoid Tumors

McDermott¹,

Kathad²,

Varma

et al. 2022

Front. Drug. Discov.

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Over the last decade the next-generation sequencing and ‘omics techniques have become indispensable tools for medicine and drug discovery. These techniques have led to an explosion of publicly available data that often goes under-utilized due to the lack of bioinformatic expertise and tools to analyze that volume of data. Here, we demonstrate the power of applying two novel computational platforms, the NCI’s CellMiner Cross Database and Lantern Pharma’s proprietary artificial intelligence (AI) and machine learning (ML) RADR® platform, to identify biological insights and potentially new target indications for the acylfulvene derivative drugs LP-100 (Irofulven) and LP-184. Analysis of multi-omics data of both drugs within CellMinerCDB generated discoveries into their mechanism of action, gene sets uniquely enriched to each drug, and how these drugs differed from existing DNA alkylating agents. Data from CellMinerCDB suggested that LP-184 and LP-100 were predicted to be effective in cancers with chromatin remodeling deficiencies, like the ultra-rare and fatal childhood cancer Atypical Teratoid Rhabdoid Tumors (ATRT). Lantern’s AI and ML RADR® platform was then utilized to build a model to test, in silico, if LP-184 would be efficacious in ATRT patients. In silico, RADR® aided in predicting that, indeed, ATRT would be sensitive to LP-184, which was then validated in vitro and in vivo. Applying computational tools and AI, like CellMinerCDB and RADR®, are novel and efficient translational approaches to drug discovery for rare cancers like ATRT.

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Mapping the Human Kinome in Response to DNA Damage

Abstract: Highlights d Catalog of the human kinome in response to different types of genotoxic stress d Synthetic vulnerability or resistance for kinases and DNAdamaging chemotherapeutics d Identification of MARK3 as a kinase in the DNA damage response

Cited by 24 publications

References 59 publications

The metabolic stress-activated checkpoint LKB1-MARK3 axis acts as a tumor suppressor in high-grade serous ovarian carcinoma

The metabolic stress-activated checkpoint LKB1-MARK3 axis acts as a tumor suppressor in high-grade serous ovarian carcinoma

Peptide fusion improves prime editing efficiency

Artificial intelligence platform, RADR®, aids in the discovery of DNA damaging agent for the ultra-rare cancer Atypical Teratoid Rhabdoid Tumors

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