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 CDK5RAP3, a New BRCA2 Partner That Regulates DNA Repair, Is Associated with Breast Cancer Survival

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 353
Author(s):  
Jordi Minguillón ◽  
María José Ramírez ◽  
Llorenç Rovirosa ◽  
Pilar Bustamante-Madrid ◽  
Cristina Camps-Fajol ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Dna Damage ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Risk ◽  
Brca2 Mutation ◽  
Ovarian Cancer Risk ◽  
Breast And Ovarian Cancer ◽  
Increased Risk

BRCA2 is essential for homologous recombination DNA repair. BRCA2 mutations lead to genome instability and increased risk of breast and ovarian cancer. Similarly, mutations in BRCA2-interacting proteins are also known to modulate sensitivity to DNA damage agents and are established cancer risk factors. Here we identify the tumor suppressor CDK5RAP3 as a novel BRCA2 helical domain-interacting protein. CDK5RAP3 depletion induced DNA damage resistance, homologous recombination and single-strand annealing upregulation, and reduced spontaneous and DNA damage-induced genomic instability, suggesting that CDK5RAP3 negatively regulates double-strand break repair in the S-phase. Consistent with this cellular phenotype, analysis of transcriptomic data revealed an association between low CDK5RAP3 tumor expression and poor survival of breast cancer patients. Finally, we identified common genetic variations in the CDK5RAP3 locus as potentially associated with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. Our results uncover CDK5RAP3 as a critical player in DNA repair and breast cancer outcomes.

scholarly journals O2: TOWARDS A LIVING BIOBANK OF SURGICALLY-RELEVANT 3-DIMENSIONAL GLIOBLASTOMA STEM CELL MODELS TO EVALUATE NOVEL THERAPEUTICS AND INTERROGATE INTRATUMOURAL HETEROGENEITY

2021 ◽  
Vol 108 (Supplement_1) ◽  
Author(s):  
O Rominiyi ◽  
A Vanderlinden ◽  
K Myers ◽  
N Gomez-Roman ◽  
D Dar ◽  
...  
Keyword(s):  
Dna Damage ◽  
Stem Cell ◽  
Cancer Biology ◽  
Residual Disease ◽  
Dna Damage Repair ◽  
Stem Cell Marker ◽  
Left Behind ◽  
Glioblastoma Stem Cell ◽  
Damage Repair ◽  
Intratumoural Heterogeneity

Abstract Introduction Glioblastoma is the most common cancer arising within the brain. Despite surgery, followed by DNA-damaging chemoradiotherapy, average survival remains between 12-15 months. Unacceptable survival rates underline the need to develop preclinical research models which recapitulate features underpinning therapeutic resistance in patients, such as intratumoural heterogeneity and treatment resistant glioblastoma stem cell (GSC) subpopulations which demonstrate elevated DNA damage response (DDR) activity. Method Tumour specimens from patients were used to generate 2D and 3D scaffold-based GSC models, with a range of preclinical survival and molecular assays used to interrogate cancer biology and assess therapeutic responses. Result We have developed a ‘living biobank’ of 20+ ex-vivo GSC models which reflect key clinicopathological diversity. These models include residual disease models based on careful macrodissection of rare en-blocpartial lobectomy specimens to liberate parallel GSC lines from the tumour core and adjacent infiltrated brain, to represent cells typically left behind after surgery. Therapeutic strategies targeting fundamental DDR processes demonstrate preclinical efficacy, for example dual inhibition of ATR and the FA DNA damage repair pathways elicits profound radiosensitisation (sensitiser enhancement ratio of 3.23 (3.03-3.49, 95%-CI)) with evidence of delayed DNA damage repair on single-cell gel electrophoresis. Finally, characterisation of our surgically-relevant resected and residual models reveals numerous divergent properties including elevated stem cell marker expression in residual models (p=0.0021), which may partially explain treatment resistance in disease left behind after surgery. Conclusion Our living biobank represents a useful resource for preclinical glioblastoma research and demonstrates the value of partnership between surgeons and laboratory-based scientists. Take-home message Our living biobank represents a useful resource for preclinical glioblastoma research and demonstrates the value of partnership between surgeons and laboratory-based scientists.

scholarly journals LINC-PINT impedes DNA repair and enhances radiotherapeutic response by targeting DNA-PKcs in nasopharyngeal cancer

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
You-hong Wang ◽  
Zhen Guo ◽  
Liang An ◽  
Yong Zhou ◽  
Heng Xu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Nasopharyngeal Cancer ◽  
Noncoding Rnas ◽  
Dependent Protein Kinase ◽  
Damage Repair ◽  
Dependent Protein ◽  
Cancer Tissues

AbstractRadioresistance continues to be the leading cause of recurrence and metastasis in nasopharyngeal cancer. Long noncoding RNAs are emerging as regulators of DNA damage and radioresistance. LINC-PINT was originally identified as a tumor suppressor in various cancers. In this study, LINC-PINT was significantly downregulated in nasopharyngeal cancer tissues than in rhinitis tissues, and low LINC-PINT expressions showed poorer prognosis in patients who received radiotherapy. We further identified a functional role of LINC-PINT in inhibiting the malignant phenotypes and sensitizing cancer cells to irradiation in vitro and in vivo. Mechanistically, LINC-PINT was responsive to DNA damage, inhibiting DNA damage repair through ATM/ATR-Chk1/Chk2 signaling pathways. Moreover, LINC-PINT increased radiosensitivity by interacting with DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and negatively regulated the expression and recruitment of DNA-PKcs. Therefore, these findings collectively support the possibility that LINC-PINT serves as an attractive target to overcome radioresistance in NPC.

scholarly journals PARP Power: A Structural Perspective on PARP1, PARP2, and PARP3 in DNA Damage Repair and Nucleosome Remodelling

2021 ◽  
Vol 22 (10) ◽  
pp. 5112
Author(s):  
Lotte van Beek ◽  
Éilís McClay ◽  
Saleha Patel ◽  
Marianne Schimpl ◽  
Laura Spagnolo ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Binding ◽  
Parp Inhibitors ◽  
Covalent Modification ◽  
Activation Mechanism ◽  
Cancer Therapies ◽  
Damage Repair ◽  
Complementary Role ◽  
Functional Understanding

Poly (ADP-ribose) polymerases (PARP) 1-3 are well-known multi-domain enzymes, catalysing the covalent modification of proteins, DNA, and themselves. They attach mono- or poly-ADP-ribose to targets using NAD+ as a substrate. Poly-ADP-ribosylation (PARylation) is central to the important functions of PARP enzymes in the DNA damage response and nucleosome remodelling. Activation of PARP happens through DNA binding via zinc fingers and/or the WGR domain. Modulation of their activity using PARP inhibitors occupying the NAD+ binding site has proven successful in cancer therapies. For decades, studies set out to elucidate their full-length molecular structure and activation mechanism. In the last five years, significant advances have progressed the structural and functional understanding of PARP1-3, such as understanding allosteric activation via inter-domain contacts, how PARP senses damaged DNA in the crowded nucleus, and the complementary role of histone PARylation factor 1 in modulating the active site of PARP. Here, we review these advances together with the versatility of PARP domains involved in DNA binding, the targets and shape of PARylation and the role of PARPs in nucleosome remodelling.

scholarly journals Differences in PARP Inhibitors for the Treatment of Ovarian Cancer: Mechanisms of Action, Pharmacology, Safety, and Efficacy

2021 ◽  
Vol 22 (8) ◽  
pp. 4203
Author(s):  
Giorgio Valabrega ◽  
Giulia Scotto ◽  
Valentina Tuninetti ◽  
Arianna Pani ◽  
Francesco Scaglione
Keyword(s):  
Ovarian Cancer ◽  
Signal Transduction ◽  
Dna Damage ◽  
Chemical Structure ◽  
Parp Inhibitors ◽  
Mechanisms Of Action ◽  
Point Of View ◽  
Safety And Efficacy ◽  
Damage Repair ◽  
Pharmacokinetic Properties

Poly(ADP-ribose) polymerases (PARP) are proteins responsible for DNA damage detection and signal transduction. PARP inhibitors (PARPi) are able to interact with the binding site for PARP cofactor (NAD+) and trapping PARP on the DNA. In this way, they inhibit single-strand DNA damage repair. These drugs have been approved in recent years for the treatment of ovarian cancer. Although they share some similarities, from the point of view of the chemical structure and pharmacodynamic, pharmacokinetic properties, these drugs also have some substantial differences. These differences may underlie the different safety profiles and activity of PARPi.

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