186 INVITED Synthetic lethal approaches as potential therapies for tumours deficient in DNA repair pathways

Abstract Helicases are enzymes that use the energy derived from ATP hydrolysis to catalyze the unwinding of DNA or RNA. The RecQ family of helicases is conserved through evolution from prokaryotes to higher eukaryotes and plays important roles in various DNA repair pathways, contributing to the maintenance of genome integrity. Despite their roles as general tumor suppressors, there is now considerable interest in exploiting RecQ helicases as synthetic lethal targets for the development of new cancer therapeutics. In this review, we summarize the latest developments in the structural and mechanistic study of RecQ helicases and discuss their roles in various DNA repair pathways. Finally, we consider the potential to exploit RecQ helicases as therapeutic targets and review the recent progress towards the development of small molecules targeting RecQ helicases as cancer therapeutics.

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A Synthetic Lethal Screen Identifies DNA Repair Pathways that Sensitize Cancer Cells to Combined ATR Inhibition and Cisplatin Treatments

PLoS ONE ◽

10.1371/journal.pone.0125482 ◽

2015 ◽

Vol 10 (5) ◽

pp. e0125482 ◽

Cited By ~ 71

Author(s):

Kareem N. Mohni ◽

Petria S. Thompson ◽

Jessica W. Luzwick ◽

Gloria G. Glick ◽

Christopher S. Pendleton ◽

...

Keyword(s):

Dna Repair ◽

Cancer Cells ◽

Synthetic Lethal ◽

Repair Pathways

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NR1D1 regulation by Ran GTPase via miR4472 identifies an essential vulnerability linked to aneuploidy in ovarian cancer

Oncogene ◽

10.1038/s41388-021-02082-z ◽

2021 ◽

Author(s):

Zied Boudhraa ◽

Kossay Zaoui ◽

Hubert Fleury ◽

Maxime Cahuzac ◽

Sophie Gilbert ◽

...

Keyword(s):

Ovarian Cancer ◽

Dna Repair ◽

Critical Role ◽

Inverse Correlation ◽

Dna Damages ◽

Ran Gtpase ◽

Synthetic Lethal ◽

Damage Repair ◽

Repair Pathways

AbstractWhile aneuploidy is a main enabling characteristic of cancers, it also creates specific vulnerabilities. Here we demonstrate that Ran inhibition targets epithelial ovarian cancer (EOC) survival through its characteristic aneuploidy. We show that induction of aneuploidy in rare diploid EOC cell lines or normal cells renders them highly dependent on Ran. We also establish an inverse correlation between Ran and the tumor suppressor NR1D1 and reveal the critical role of Ran/NR1D1 axis in aneuploidy-associated endogenous DNA damage repair. Mechanistically, we show that Ran, through the maturation of miR4472, destabilizes the mRNA of NR1D1 impacting several DNA repair pathways. We showed that NR1D1 interacts with both PARP1 and BRCA1 leading to the inhibition of DNA repair. Concordantly, loss of Ran was associated with NR1D1 induction, accumulation of DNA damages, and lethality of aneuploid EOC cells. Our findings suggest a synthetic lethal strategy targeting aneuploid cells based on their dependency to Ran.

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Abstract 2006: Sequencing of mismatch repair deficient tumors identifies a synthetic lethal interaction with other DNA repair pathways.

10.1158/1538-7445.am2013-2006 ◽

2013 ◽

Author(s):

Betül T. Yesilyurt ◽

Hui Zhao ◽

Xavier Sagaert ◽

Lieve Coenegrachts ◽

Zeynep Kalender ◽

...

Keyword(s):

Dna Repair ◽

Mismatch Repair ◽

Synthetic Lethal Interaction ◽

Synthetic Lethal ◽

Repair Pathways

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Targeting the Fanconi Anemia Pathway to Identify Tailored Anticancer Therapeutics

Anemia ◽

10.1155/2012/481583 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 11

Author(s):

Chelsea Jenkins ◽

Jenny Kan ◽

Maureen E. Hoatlin

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Fanconi Anemia ◽

Cancer Therapeutics ◽

Core Complex ◽

Synthetic Lethal ◽

Interstrand Cross Links ◽

Cross Links ◽

Repair Pathways ◽

Repair Genes

The Fanconi Anemia (FA) pathway consists of proteins involved in repairing DNA damage, including interstrand cross-links (ICLs). The pathway contains an upstream multiprotein core complex that mediates the monoubiquitylation of the FANCD2 and FANCI heterodimer, and a downstream pathway that converges with a larger network of proteins with roles in homologous recombination and other DNA repair pathways. Selective killing of cancer cells with an intact FA pathway but deficient in certain other DNA repair pathways is an emerging approach to tailored cancer therapy. Inhibiting the FA pathway becomes selectively lethal when certain repair genes are defective, such as the checkpoint kinase ATM. Inhibiting the FA pathway in ATM deficient cells can be achieved with small molecule inhibitors, suggesting that new cancer therapeutics could be developed by identifying FA pathway inhibitors to treat cancers that contain defects that are synthetic lethal with FA.

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Histone methylation can either promote or reduce cellular radiosensitivity by regulating DNA repair pathways

Mutation Research/Reviews in Mutation Research ◽

10.1016/j.mrrev.2020.108362 ◽

2021 ◽

Vol 787 ◽

pp. 108362

Author(s):

Yuchuan Zhou ◽

Chunlin Shao

Keyword(s):

Dna Repair ◽

Histone Methylation ◽

Cellular Radiosensitivity ◽

Repair Pathways

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Targeting DNA Repair and Chromatin Crosstalk in Cancer Therapy

Cancers ◽

10.3390/cancers13030381 ◽

2021 ◽

Vol 13 (3) ◽

pp. 381

Author(s):

Danielle P. Johnson ◽

Mahesh B. Chandrasekharan ◽

Marie Dutreix ◽

Srividya Bhaskara

Keyword(s):

Dna Repair ◽

Cancer Therapy ◽

Therapeutic Intervention ◽

Synthetic Lethality ◽

Checkpoint Proteins ◽

Cellular Processes ◽

Repair Pathways ◽

Made In

Aberrant DNA repair pathways that underlie developmental diseases and cancers are potential targets for therapeutic intervention. Targeting DNA repair signal effectors, modulators and checkpoint proteins, and utilizing the synthetic lethality phenomena has led to seminal discoveries. Efforts to efficiently translate the basic findings to the clinic are currently underway. Chromatin modulation is an integral part of DNA repair cascades and an emerging field of investigation. Here, we discuss some of the key advancements made in DNA repair-based therapeutics and what is known regarding crosstalk between chromatin and repair pathways during various cellular processes, with an emphasis on cancer.

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