scholarly journals A meta-analysis of reversion mutations in BRCA genes identifies signatures of DNA end-joining repair mechanisms driving therapy resistance

2021 ◽  
Vol 32 (1) ◽  
pp. 103-112
Author(s):  
L. Tobalina ◽  
J. Armenia ◽  
E. Irving ◽  
M.J. O'Connor ◽  
J.V. Forment
Keyword(s):  
Meta Analysis ◽  
Therapy Resistance ◽  
End Joining ◽  
Brca Genes ◽  
Repair Mechanisms

scholarly journals A meta-analysis of clinical cases of reversion mutations in BRCA genes identifies signatures of DNA end-joining repair mechanisms driving therapy resistance

2020 ◽  
Author(s):  
Luis Tobalina ◽  
Joshua Armenia ◽  
Elsa Irving ◽  
Mark J. O’Connor ◽  
Josep V. Forment
Keyword(s):  
Dna Repair ◽  
Meta Analysis ◽  
Therapy Resistance ◽  
List Type ◽  
End Joining ◽  
Pharmacological Inhibition ◽  
Repair Mechanisms ◽  
Drug Treatments ◽  
Repair Pathways ◽  
Clinical Cases

AbstractGermline mutations in the BRCA1 or BRCA2 genes predispose to hereditary breast and ovarian cancer and, mostly in the case of BRCA2, are also prevalent in cases of pancreatic and prostate malignancies. Tumours from these patients tend to lose both copies of the wild type BRCA gene, which makes them exquisitely sensitive to platinum drugs and PARP inhibitors (PARPi), treatments of choice in these disease settings. Reversion secondary mutations with the capacity of restoring BRCA protein expression have been documented in the literature as bona fide mechanisms of resistance to these treatments. Here, we perform a detailed analysis of clinical cases of reversion mutations described in BRCA1 and BRCA2, which underlines the different importance of BRCA protein domains in contributing to resistance and the potential key role of mutagenic end-joining DNA repair pathways in generating reversions. Our analyses suggest that pharmacological inhibition of these repair pathways could improve durability of drug treatments and highlights potential interventions to both prevent the appearance of reversions and provide new therapeutic opportunities after their acquisition.HighlightsComprehensive analysis of reversion mutations in BRCA genes identified in clinical cases of resistance to platinum or PARPiRevertant proteins devoid of parts of the original sequence, identifying key protein functions involved in resistanceHypomorph revertant BRCA proteins suggest potential new therapeutic opportunities to overcome resistancePrevalence of mutational end-joining DNA repair mechanisms leading to reversions, especially in those affecting BRCA2Pharmacological inhibition of mutational end-joining DNA repair could improve durability of drug treatments

scholarly journals Regulatory and Functional Involvement of Long Non-Coding RNAs in DNA Double-Strand Break Repair Mechanisms

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1506
Author(s):  
Angelos Papaspyropoulos ◽  
Nefeli Lagopati ◽  
Ioanna Mourkioti ◽  
Andriani Angelopoulou ◽  
Spyridon Kyriazis ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Strand Break ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Dsb Repair ◽  
Repair Mechanisms ◽  
Non Coding Rnas ◽  
Repair Pathways ◽  
Non Homologous End Joining ◽  
Living Organisms

Protection of genome integrity is vital for all living organisms, particularly when DNA double-strand breaks (DSBs) occur. Eukaryotes have developed two main pathways, namely Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR), to repair DSBs. While most of the current research is focused on the role of key protein players in the functional regulation of DSB repair pathways, accumulating evidence has uncovered a novel class of regulating factors termed non-coding RNAs. Non-coding RNAs have been found to hold a pivotal role in the activation of DSB repair mechanisms, thereby safeguarding genomic stability. In particular, long non-coding RNAs (lncRNAs) have begun to emerge as new players with vast therapeutic potential. This review summarizes important advances in the field of lncRNAs, including characterization of recently identified lncRNAs, and their implication in DSB repair pathways in the context of tumorigenesis.

scholarly journals Androgen Receptor Signaling in Prostate Cancer Genomic Subtypes

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3272
Author(s):  
Lauren K. Jillson ◽  
Gabriel A. Yette ◽  
Teemu D. Laajala ◽  
Wayne D. Tilley ◽  
James C. Costello ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Targeted Therapies ◽  
Meta Analysis ◽  
Therapy Resistance ◽  
Androgen Receptor Signaling ◽  
Genomic Changes ◽  
Risk Patients ◽  
Important Pathway ◽  
Therapy Option

While many prostate cancer (PCa) cases remain indolent and treatable, others are aggressive and progress to the metastatic stage where there are limited curative therapies. Androgen receptor (AR) signaling remains an important pathway for proliferative and survival programs in PCa, making disruption of AR signaling a viable therapy option. However, most patients develop resistance to AR-targeted therapies or inherently never respond. The field has turned to PCa genomics to aid in stratifying high risk patients, and to better understand the mechanisms driving aggressive PCa and therapy resistance. While alterations to the AR gene itself occur at later stages, genomic changes at the primary stage can affect the AR axis and impact response to AR-directed therapies. Here, we review common genomic alterations in primary PCa and their influence on AR function and activity. Through a meta-analysis of multiple independent primary PCa databases, we also identified subtypes of significantly co-occurring alterations and examined their combinatorial effects on the AR axis. Further, we discussed the subsequent implications for response to AR-targeted therapies and other treatments. We identified multiple primary PCa genomic subtypes, and given their differing effects on AR activity, patient tumor genetics may be an important stratifying factor for AR therapy resistance.

scholarly journals Phosphorylation: The Molecular Switch of Double-Strand Break Repair

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
K. C. Summers ◽  
F. Shen ◽  
E. A. Sierra Potchanant ◽  
E. A. Phipps ◽  
R. J. Hickey ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Genomic Stability ◽  
Molecular Switches ◽  
Strand Break ◽  
Nonhomologous End Joining ◽  
End Joining ◽  
Brca1 And Brca2 ◽  
Damage Response ◽  
Repair Mechanisms ◽  
Repair Pathways

Repair of double-stranded breaks (DSBs) is vital to maintaining genomic stability. In mammalian cells, DSBs are resolved in one of the following complex repair pathways: nonhomologous end-joining (NHEJ), homologous recombination (HR), or the inclusive DNA damage response (DDR). These repair pathways rely on factors that utilize reversible phosphorylation of proteins as molecular switches to regulate DNA repair. Many of these molecular switches overlap and play key roles in multiple pathways. For example, the NHEJ pathway and the DDR both utilize DNA-PK phosphorylation, whereas the HR pathway mediates repair with phosphorylation of RPA2, BRCA1, and BRCA2. Also, the DDR pathway utilizes the kinases ATM and ATR, as well as the phosphorylation of H2AX and MDC1. Together, these molecular switches regulate repair of DSBs by aiding in DSB recognition, pathway initiation, recruitment of repair factors, and the maintenance of repair mechanisms.

Endocrine therapy-based strategies with different endocrine sensitivity statuses for hormone receptor positive/HER2 negative metastatic breast cancer: A network meta-analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1062-1062
Author(s):  
Jiani Wang ◽  
Yiqun Han ◽  
Jiayu Wang ◽  
Binghe Xu
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Endocrine Therapy ◽  
Hormone Receptor ◽  
Meta Analysis ◽  
Metastatic Breast ◽  
Therapy Resistance ◽  
Optimal Treatment ◽  
Hormone Receptor Positive ◽  
Direct Head

1062 Background: Novel endocrine therapies (ETs) and targeted therapeutic regimens have been developed to dramatically improve the outcome of hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer (MBC). Since the absence of direct head-to-head comparisons for all regimens, decision-making guidelines are urgently needed for different endocrine sensitivity statuses. This study is to evaluate the efficacy of ET-based regimens in patients with HR+/HER2- MBC and to assess the heterogeneity among different compounds with a particular focus on their ability to improve survival outcomes. Methods: This network meta-analysis of phase II/III randomized controlled trials (RCTs) with at least one ET in HR+/HER2- MBC were enrolled. Based on the endocrine responses, participants were stratified into endocrine therapy sensitivity (ETS) and endocrine therapy resistance (ETR) groups. Primary endpoints, including progression-free survival (PFS) and overall survival (OS), were assessed by bayesian algorithms and primarily measured as surface under the cumulative ranking curve (SUCRA). Results: A total of 42 trials (22917 patients) were included. Regarding PFS, cyclin-dependent kinases 4/6 inhibitors (CDK4/6i) +fulvestrant 500mg (F500) was recommended for the ETS group (SUCRA = 76.92%), while chemotherapy was considered as the most effective option for the ETR group (SUCRA = 73.47%). For visceral metastases, CDK4/6i +aromatase inhibitors (AIs) could provide the extreme efficacy for the ETS group (SUCRA = 63.27%) while the CDK4/6i +F500 (SUCRA = 76.17%) as the prior regimen for the ETR group. For bone-only disease, CDK4/6i+F500 was preferred for both the ETS (SUCRA = 67.04%) and the ETR (SUCRA = 70.24%) group. Concerning OS, CDK4/6i+tamoxifen was estimated as the first-rank regimen for the ETS subgroup (SUCRA = 67.04%) and chemotherapy for the ETR subgroup (SUCRA = 60.02%). Regarding resistance category, abemaciclib +F500 was likely the best option with PFS, for both primary (SUCRA = 69.19%) and secondary ETR (SUCRA = 69.09%) settings, as well as primary ETR associated with OS improvement (SUCRA = 67.67%). Pictilisib +F500 could be the optimal treatment with OS for secondary ETR (SUCRA = 60.50%)group. Conclusions: The results showed that CDK4/6i + F500 was probably the most promising option in ETS, visceral ETR and bone-only disease settings in terms of PFS. OS subgroup analysis showed that different endocrine sensitivity statuses required various optimal treatment strategies.

Double strand break (DSB) repair pathways in plants and their application in genome engineering

2021 ◽  
pp. 27-62
Author(s):  
Natalja Beying ◽  
◽  
Carla Schmidt ◽  
Holger Puchta ◽  
◽  
...  
Keyword(s):  
Genome Engineering ◽  
Plant Cells ◽  
Strand Break ◽  
End Joining ◽  
Dsb Repair ◽  
Strand Breaks ◽  
Repair Mechanisms ◽  
Repair Pathways ◽  
Non Homologous End Joining ◽  
Underlying Mechanisms

In genome engineering, after targeted induction of double strand breaks (DSBs) researchers take advantage of the organisms’ own repair mechanisms to induce different kinds of sequence changes into the genome. Therefore, understanding of the underlying mechanisms is essential. This chapter will review in detail the two main pathways of DSB repair in plant cells, non-homologous end joining (NHEJ) and homologous recombination (HR) and sum up what we have learned over the last decades about them. We summarize the different models that have been proposed and set these into relation with the molecular outcomes of different classes of DSB repair. Moreover, we describe the factors that have been identified to be involved in these pathways. Applying this knowledge of DSB repair should help us to improve the efficiency of different types of genome engineering in plants.

scholarly journals Databases and Bioinformatics Tools for the Study of DNA Repair

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Kaja Milanowska ◽  
Kristian Rother ◽  
Janusz M. Bujnicki
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Excision Repair ◽  
Uv Light ◽  
Dna Lesions ◽  
Environmental Chemicals ◽  
Nonhomologous End Joining ◽  
End Joining ◽  
Repair Mechanisms ◽  
Base Excision

DNA is continuously exposed to many different damaging agents such as environmental chemicals, UV light, ionizing radiation, and reactive cellular metabolites. DNA lesions can result in different phenotypical consequences ranging from a number of diseases, including cancer, to cellular malfunction, cell death, or aging. To counteract the deleterious effects of DNA damage, cells have developed various repair systems, including biochemical pathways responsible for the removal of single-strand lesions such as base excision repair (BER) and nucleotide excision repair (NER) or specialized polymerases temporarily taking over lesion-arrested DNA polymerases during the S phase in translesion synthesis (TLS). There are also other mechanisms of DNA repair such as homologous recombination repair (HRR), nonhomologous end-joining repair (NHEJ), or DNA damage response system (DDR). This paper reviews bioinformatics resources specialized in disseminating information about DNA repair pathways, proteins involved in repair mechanisms, damaging agents, and DNA lesions.

scholarly journals Harnessing endogenous repair mechanisms for targeted gene knock-in of bovine embryos

2020 ◽  
Author(s):  
Joseph R. Owen ◽  
Sadie L. Hennig ◽  
Bret R. McNabb ◽  
Jason C. Lin ◽  
Amy E. Young ◽  
...  
Keyword(s):  
Dna Sequences ◽  
Bovine Genome ◽  
Direct Injection ◽  
End Joining ◽  
Homology Directed Repair ◽  
Livestock Breeding ◽  
Repair Mechanisms ◽  
Dividing Cells ◽  
The One ◽  
Donor Template

ABSTRACTIntroducing useful traits into livestock breeding programs through gene knock-ins has proven challenging. Typically, targeted insertions have been performed in cell lines, followed by somatic cell nuclear transfer cloning, which can be inefficient. An alternative is to introduce genome editing reagents and a homologous recombination (HR) donor template into embryos to trigger homology-directed repair (HDR). However, the HR pathway is primarily restricted to actively dividing cells (S/G2-phase) and its efficiency is low in zygotes, especially for the introduction of large DNA sequences. The homology-mediated end joining (HMEJ)-based strategy harnesses HDR by direct injection of embryos, and has been shown to have an improved knock-in efficiency in non-dividing cells. The knock-in efficiency for a 1.8kb gene was contrasted when combining a gRNA/Cas9 ribonucleoprotein complex with either a traditional HR donor template, or a HMEJ template in bovine zygotes. The HMEJ template resulted in a significantly higher rate of gene knock-in as compared to the HR template (37.0% and 13.8%; P < 0.05). Additionally, more than a third of the knock-in embryos (36.9%) were non-mosaic. This approach will facilitate the one-step introduction of gene constructs at a specific location of the bovine genome and contribute to the next generation of elite cattle.

scholarly journals BRCA Genes: The Role in Genome Stability, Cancer Stemness and Therapy Resistance

2019 ◽  
Vol 10 (9) ◽  
pp. 2109-2127 ◽  
Author(s):  
Ielizaveta Gorodetska ◽  
Iryna Kozeretska ◽  
Anna Dubrovska
Keyword(s):  
Genome Stability ◽  
Therapy Resistance ◽  
Cancer Stemness ◽  
Brca Genes

scholarly journals Target-specific precision of CRISPR-mediated genome editing

2018 ◽  
Author(s):  
Anob M. Chakrabarti ◽  
Tristan Henser-Brownhill ◽  
Josep Monserrat ◽  
Anna R. Poetsch ◽  
Nicholas M. Luscombe ◽  
...  
Keyword(s):  
Dna Repair ◽  
Human Cells ◽  
End Joining ◽  
Single Nucleotide ◽  
Dna Repair Mechanisms ◽  
Wide Range ◽  
Repair Mechanisms ◽  
Dna Editing ◽  
Nucleotide Insertions ◽  
Eukaryotic Genomes

ABSTRACTThe CRISPR-Cas9 system has successfully been adapted to edit the genome of various organisms. However, our ability to predict editing accuracy, efficacy and outcome at specific sites is limited by an incomplete understanding of how the bacterial system interacts with eukaryotic genomes and DNA repair machineries. Here, we performed the largest comparison of indel profiles to date, examining over one thousand sites in the genome of human cells, and uncovered general principles guiding CRISPR-mediated DNA editing. We find that precision of DNA editing varies considerably among sites, with some targets showing one highly-preferred indel and others displaying a wide range of infrequent indels. Editing precision correlates with editing efficiency, homology-associated end-joining for both insertions and deletions, and a preference for single-nucleotide insertions. Precise targets and the identity of their preferred indel can be predicted based on simple rules that mainly depend on the fourth nucleotide upstream of the PAM sequence. Regardless of precision, site-specific indel profiles are highly robust and depend on both DNA sequence and chromatin features. Our findings have important implications for clinical applications of CRISPR technology and reveal general patterns of broken end-joining that can inform us on DNA repair mechanisms in human cells.

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