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

Oncogene ◽  
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.

scholarly journals Role of Biomarkers in the Development of PARP Inhibitors

2016 ◽  
Vol 8s1 ◽  
pp. BIC.S36679 ◽  
Author(s):  
Bratati Ganguly ◽  
Sonia C. Dolfi ◽  
Lorna Rodriguez-Rodriguez ◽  
Shridar Ganesan ◽  
Kim M. Hirshfield
Keyword(s):  
Dna Repair ◽  
Critical Role ◽  
Parp Inhibitors ◽  
Resistance Mechanisms ◽  
Parp Inhibition ◽  
Technological Advances ◽  
Damage Repair ◽  
Selection For ◽  
Defective Dna Repair

Defects in DNA repair lead to genomic instability and play a critical role in cancer development. Understanding the process by which DNA damage repair is altered or bypassed in cancer may identify novel therapeutic targets and lead to improved patient outcomes. Poly(adenosine diphosphateribose) polymerase 1 (PARP1) has an important role in DNA repair, and novel therapeutics targeting PARP1 have been developed to treat cancers with defective DNA repair pathways. Despite treatment successes with PARP inhibitors (PARPi), intrinsic and acquired resistances have been observed. Preclinical studies and clinical trials in cancer suggest that combination therapy using PARPi and platinating agents is more effective than monotherapy in circumventing drug resistance mechanisms. Additionally, identification of biomarkers in response to PARPi will lead to improved patient selection for targeted cancer treatment. Recent technological advances have provided the necessary tools to examine many potential avenues to develop such biomarkers. This review examines the mechanistic rationale of PARP inhibition and potential biomarkers in their development for personalized therapy.

scholarly journals The emerging role of RNAs in DNA damage repair

2017 ◽  
Vol 24 (4) ◽  
pp. 580-587 ◽  
Author(s):  
Ben R Hawley ◽  
Wei-Ting Lu ◽  
Ania Wilczynska ◽  
Martin Bushell
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Critical Role ◽  
Repair Process ◽  
Rna Molecules ◽  
Processing Enzymes ◽  
Damage Repair ◽  
New Findings ◽  
Integral Role ◽  
Repair Mechanisms

Abstract Many surveillance and repair mechanisms exist to maintain the integrity of our genome. All of the pathways described to date are controlled exclusively by proteins, which through their enzymatic activities identify breaks, propagate the damage signal, recruit further protein factors and ultimately resolve the break with little to no loss of genetic information. RNA is known to have an integral role in many cellular pathways, but, until very recently, was not considered to take part in the DNA repair process. Several reports demonstrated a conserved critical role for RNA-processing enzymes and RNA molecules in DNA repair, but the biogenesis of these damage-related RNAs and their mechanisms of action remain unknown. We will explore how these new findings challenge the idea of proteins being the sole participants in the response to DNA damage and reveal a new and exciting aspect of both DNA repair and RNA biology.

scholarly journals Regulation of the cognitive aging process by the transcriptional repressor RP58

2021 ◽  
Author(s):  
Tomoko Tanaka ◽  
Shinobu Hirai ◽  
Hiroyuki Manabe ◽  
Kentaro Endo ◽  
Hiroko Shimbo ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Knockout Mice ◽  
Cognitive Aging ◽  
Critical Role ◽  
Harmful Effect ◽  
Transcriptional Repressor ◽  
Repair Pathway ◽  
Wild Type

Aging involves a decline in physiology which is a natural event in all living organisms. An accumulation of DNA damage contributes to the progression of aging. DNA is continually damaged by exogenous sources and endogenous sources. If the DNA repair pathway operates normally, DNA damage is not life threatening. However, impairments of the DNA repair pathway may result in an accumulation of DNA damage, which has a harmful effect on health and causes an onset of pathology. RP58, a zinc-finger transcriptional repressor, plays a critical role in cerebral cortex formation. Recently, it has been reported that the expression level of RP58 decreases in the aged human cortex. Furthermore, the role of RP58 in DNA damage is inferred by the involvement of DNMT3, which acts as a co-repressor for RP58, in DNA damage. Therefore, RP58 may play a crucial role in the DNA damage associated with aging. In the present study, we investigated the role of RP58 in aging. We used RP58 hetero-knockout and wild-type mice in adolescence, adulthood, or old age. We performed immunohistochemistry to determine whether microglia and DNA damage markers responded to the decline in RP58 levels. Furthermore, we performed an object location test to measure cognitive function, which decline with age. We found that the wild-type mice showed an increase in single-stranded DNA and gamma-H2AX foci. These results indicate an increase in DNA damage or dysfunction of DNA repair mechanisms in the hippocampus as age-related changes. Furthermore, we found that, with advancing age, both the wild-type and hetero-knockout mice showed an impairment of spatial memory for the object and increase in reactive microglia in the hippocampus. However, the RP58 hetero-knockout mice showed these symptoms earlier than the wild-type mice did. These results suggest that a decline in RP58 level may lead to the progression of aging.

scholarly journals RecQ helicases in DNA repair and cancer targets

2020 ◽  
Vol 64 (5) ◽  
pp. 819-830
Author(s):  
Joseph A. Newman ◽  
Opher Gileadi
Keyword(s):  
Dna Repair ◽  
Small Molecules ◽  
Atp Hydrolysis ◽  
Cancer Therapeutics ◽  
Genome Integrity ◽  
Mechanistic Study ◽  
Synthetic Lethal ◽  
Recq Helicases ◽  
Repair Pathways ◽  
Higher Eukaryotes

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.

Critical Role of Lysophospholipids in the Pathophysiology, Diagnosis, and Management of Ovarian Cancer

2002 ◽  
pp. 259-283 ◽  
Author(s):  
Gordon B. Mills ◽  
Astrid Eder ◽  
Xianjun Fang ◽  
Yutaka Hasegawa ◽  
Muling Mao ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Critical Role ◽  
Diagnosis And Management

scholarly journals A Review on DNA Repair Inhibition by PARP Inhibitors in Cancer Therapy

Folia Medica ◽  
2018 ◽  
Vol 60 (1) ◽  
pp. 39-47 ◽  
Author(s):  
Ashish P. Shah ◽  
Chhagan N. Patel ◽  
Dipen K. Sureja ◽  
Kirtan P. Sanghavi
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cancer Therapy ◽  
Repair Process ◽  
Parp Inhibitors ◽  
Brca Mutations ◽  
Development Of Resistance ◽  
Damage Repair ◽  
Future Therapy

AbstractThe DNA repair process protects the cells from DNA damaging agent by multiple pathways. Majority of the cancer therapy cause DNA damage which leads to apoptosis. The cell has natural ability to repair this damage which ultimately leads to development of resistance of drugs. The key enzymes involved in DNA repair process are poly(ADP-ribose) (PAR) and poly(ADP-ribose) polymerases (PARP). Tumor cells repair their defective gene via defective homologues recombination (HR) in the presence of enzyme PARP. PARP inhibitors inhibit the enzyme poly(ADP-ribose) polymerases (PARPs) which lead to apoptosis of cancer cells. Current clinical data shows the role of PARP inhibitors is not restricted to BRCA mutations but also effective in HR dysfunctions related tumors. Therefore, investigation in this area could be very helpful for future therapy of cancer. This review gives detail information on the role of PARP in DNA damage repair, the role of PARP inhibitors and chemistry of currently available PARP inhibitors.

scholarly journals Regulation and pharmacological targeting of RAD51 in cancer

NAR Cancer ◽  
2020 ◽  
Vol 2 (3) ◽  
Author(s):  
McKenzie K Grundy ◽  
Ronald J Buckanovich ◽  
Kara A Bernstein
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Homologous Recombination ◽  
Patient Outcomes ◽  
Cancer Biology ◽  
Cancer Resistance ◽  
Breast And Ovarian Cancer ◽  
Resistance To Therapy ◽  
Damage Repair

Abstract Regulation of homologous recombination (HR) is central for cancer prevention. However, too little HR can increase cancer incidence, whereas too much HR can drive cancer resistance to therapy. Importantly, therapeutics targeting HR deficiency have demonstrated a profound efficacy in the clinic improving patient outcomes, particularly for breast and ovarian cancer. RAD51 is central to DNA damage repair in the HR pathway. As such, understanding the function and regulation of RAD51 is essential for cancer biology. This review will focus on the role of RAD51 in cancer and beyond and how modulation of its function can be exploited as a cancer therapeutic.

scholarly journals Critical role of lysine 134 methylation on histone H2AX for γ-H2AX production and DNA repair

2014 ◽  
Vol 5 (1) ◽  
Author(s):  
Kenbun Sone ◽  
Lianhua Piao ◽  
Makoto Nakakido ◽  
Koji Ueda ◽  
Thomas Jenuwein ◽  
...  
Keyword(s):  
Dna Repair ◽  
Critical Role ◽  
Histone H2ax

Integrative analyses of signaling and DNA damage repair pathways in patient-derived xenograft (PDX) models from NCI’s patient-derived models repository (PDMR).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3111-3111
Author(s):  
Biswajit Das ◽  
Yvonne A. Evrard ◽  
Li Chen ◽  
Rajesh Patidar ◽  
Tomas Vilimas ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Large Fraction ◽  
Dna Damage Repair ◽  
Damage Repair ◽  
Pathway Activation ◽  
Integrative Analyses ◽  
Multiple Data Sets ◽  
Repair Pathways ◽  
Pdx Models

3111 Background: Patient-derived xenografts (PDXs) are increasingly being used in translational cancer research for preclinical drug efficacy studies. The National Cancer Institute (NCI) has developed a Patient-Derived Models Repository (NCI PDMR; pdmr.cancer.gov ) of PDXs with clinical annotation, proteomics, and comprehensive genomic datasets to facilitate these studies. Here, we present an integrative genomic, transcriptomic, and proteomic analysis of critical signaling and DNA damage repair pathways in these PDX models, which represent 9 common and multiple rare tumor histologies. Methods: 304 PDX models from 294 patients were established from various solid tumor histologies from patients with primary or metastatic cancer. Whole Exome Sequencing, RNA-Seq and Reverse Phase Protein Array (RPPA) were performed on 2-9 PDXs per model across multiple passages. An integrative workflow was applied on multiple data sets to detect pathway activation. Results: We profiled 10 signaling and 5 DNA repair pathways in the PDMR dataset. We observed that: (i) a large fraction (40%) of PDX models have at least 1 targetable mutation in the RTK/RAS and/or PIK3CA pathways; (ii) 131 models (45%) have putative driver and oncogenic mutations and copy number variants (CNVs) in the WNT, TGFRb , NRF2 and NOTCH pathways. In addition, 17% of PDX models have targetable mutations in DNA damage repair pathways and 20 PDMR models have a DNA mismatch repair defect (MSI-H). We confirmed activation of the signaling pathways in a subset of PDX models by pathway enrichment analysis on gene expression data from RNASeq and phosphoprotein-specific antibody binding data from RPPA. Activation of DNA repair processes was confirmed by enrichment of relevant mutational signatures and loss of heterozygosity in these PDX models. Conclusions: Genomic analysis of NCI PDMR models revealed that a large fraction have clinically relevant somatic alterations in key signaling and DNA damage repair pathways. Further integrative analyses with matched transcriptomic and proteomic profiles confirmed pathway activation in a subset of these models, which may prioritize them for preclinical drug studies.

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