MND1 and PSMC3IP control PARP inhibitor sensitivity in mitotic cells

Zelceski, Anabel; Francica, Paola; Lingg, Lea; Mutlu, Merve; Stok, Colin; Liptay, Martin; Alexander, John J.; Baxter, Joseph S.; Brough, Rachel; Gulati, Aditi; Haider, Syed; Raghunandan, Maya; Song, Feifei; Sridhar, Sandhya; Forment, Josep V.; O’Connor, Mark J.; Davies, Barry R.; Vugt, Marcel A.T.M. van; Krastev, Dragomir B.; Pettitt, Stephen J.; Tutt, Andrew; Rottenberg, Sven; Lord, Christopher J.

doi:10.1016/j.celrep.2023.112484

Cited by 3 publications

(1 citation statement)

References 72 publications

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“…Genome‐wide CRISPR screens were conducted as described in [ 32 ]. Doxycycline inducible SpCas9‐expressing (Horizon, #CAS11229) cells were generated by transduction (Dharmacon, Waterbeach, UK), followed by Blasticidin selection (7 μg·mL −1 ).…”

Section: Methodsmentioning

confidence: 99%

Cancer‐associated FBXW7 loss is synthetic lethal with pharmacological targeting of CDC7

Baxter,

Brough,

Krastev

et al. 2023

Molecular Oncology

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The F‐box and WD repeat domain containing 7 (FBXW7) tumour suppressor gene encodes a substrate‐recognition subunit of Skp, cullin, F‐box (SCF)‐containing complexes. The tumour‐suppressive role of FBXW7 is ascribed to its ability to drive ubiquitination and degradation of oncoproteins. Despite this molecular understanding, therapeutic approaches that target defective FBXW7 have not been identified. Using genome‐wide clustered regularly interspaced short palindromic repeats (CRISPR)‐Cas9 screens, focussed RNA‐interference screens and whole and phospho‐proteome mass spectrometry profiling in multiple FBXW7 wild‐type and defective isogenic cell lines, we identified a number of FBXW7 synthetic lethal targets, including proteins involved in the response to replication fork stress and proteins involved in replication origin firing, such as cell division cycle 7‐related protein kinase (CDC7) and its substrate, DNA replication complex GINS protein SLD5 (GINS4). The CDC7 synthetic lethal effect was confirmed using small‐molecule inhibitors. Mechanistically, FBXW7/CDC7 synthetic lethality is dependent upon the replication factor telomere‐associated protein RIF1 (RIF1), with RIF1 silencing reversing the FBXW7‐selective effects of CDC7 inhibition. 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.

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Section: Methodsmentioning

confidence: 99%

Cancer‐associated FBXW7 loss is synthetic lethal with pharmacological targeting of CDC7

Baxter,

Brough,

Krastev

et al. 2023

Molecular Oncology

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Mapping the Genetic Interaction Network of PARP inhibitor Response

Simpson,

Ling,

Jing

et al. 2023

Preprint

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Genetic interactions have long informed our understanding of the coordinated proteins and pathways that respond to DNA damage in mammalian cells, but systematic interrogation of the genetic network underlying that system has yet to be achieved. Towards this goal, we measured 147,153 pairwise interactions among genes implicated in PARP inhibitor (PARPi) response. Evaluating genetic interactions at this scale, with and without exposure to PARPi, revealed hierarchical organization of the pathways and complexes that maintain genome stability during normal growth and defined changes that occur upon accumulation of DNA lesions due to cytotoxic doses of PARPi. We uncovered unexpected relationships among DNA repair genes, including context-specific buffering interactions between the minimally characterized AUNIP and BRCA1-A complex genes. Our work thus establishes a foundation for mapping differential genetic interactions in mammalian cells and provides a comprehensive resource for future studies of DNA repair and PARP inhibitors.

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Integrative Pan-Cancer Analysis Reveals the Oncogenic Role of MND1 and Validation of MND1’s Role in Breast Cancer

Zhang,

Xiao,

Zhu

et al. 2024

JIR

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Purpose Meiotic nuclear division 1 (MND1) is a meiosis-specific protein that promotes lung adenocarcinoma progression. However, its expression and biological function across cancers remain largely unexplored. Patients and Methods The expression, prognostic significance, mutation status, and methylation profile of MND1 in various cancers were comprehensively analyzed using the TIMER, GTEX, Kaplan-Meier plotter, cBioPortal, and GSCA databases. Additionally, we constructed a PPI network, enrichment analysis and single-cell transcriptomic sequencing to elucidate the underlying mechanism of MND1. Furthermore, we investigated the association between MND1 expression and drug sensitivity using CellMiner. Moreover, we also explored the correlation between MND1 expression and immune infiltration. Finally, we validated the functional role of MND1 in breast cancer through IHC staining, CCK8, EdU, colony formation, and flow cytometry assays. Results MND1 has been reported to be highly expressed in Pan-cancer, High MND1 expression was significantly associated with poor prognosis in cancers. Additionally, MND1 mutation frequency is high in most cancers, and its expression correlates with methylation. Furthermore, MND1 expression significantly correlates with immune checkpoint blockade (ICB) markers, including PD-L1, PD-1, and CTLA-4. The PPI network reveals interactions between MND1 and PSMC3IP, BRCA1, and BRCA2. Enrichment analysis and single-cell sequencing indicate that MND1 positively correlates with cell cycle. ROC curve reveals favorable diagnostic efficacy of MND1 in breast cancer. In vitro, MND1 overexpression promotes breast cancer cell proliferation and increases the expression of key cell cycle regulators (CDK4, CDK6, and cyclin D3), accelerating the G1/S phase transition and leading to abnormal breast cancer cell proliferation. The immunohistochemical analysis revealed a robust expression of MND1 in breast cancer tissues, exhibiting a significant positive correlation with PD-L1 and FOXP3. Conclusion MND1 is an oncogene and may serve as a biomarker for cancer prognosis and immunotherapy. Targeting MND1 may be a potential tumor treatment strategy.

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MND1 and PSMC3IP control PARP inhibitor sensitivity in mitotic cells

Cited by 3 publications

References 72 publications

Cancer‐associated FBXW7 loss is synthetic lethal with pharmacological targeting of CDC7

Cancer‐associated FBXW7 loss is synthetic lethal with pharmacological targeting of CDC7

Mapping the Genetic Interaction Network of PARP inhibitor Response

Integrative Pan-Cancer Analysis Reveals the Oncogenic Role of MND1 and Validation of MND1’s Role in Breast Cancer

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