scholarly journals The Major DNA Repair Pathway after Both Proton and Carbon-Ion Radiation is NHEJ, but the HR Pathway is More Relevant in Carbon Ions

2015 ◽  
Vol 183 (3) ◽  
pp. 345-356 ◽  
Author(s):  
Ariungerel Gerelchuluun ◽  
Eri Manabe ◽  
Takaaki Ishikawa ◽  
Lue Sun ◽  
Kazuya Itoh ◽  
...  
Keyword(s):  
Dna Repair ◽  
Carbon Ions ◽  
Repair Pathway ◽  
Carbon Ion

Fanconi Anemia DNA Repair Pathway as a New Mechanism to Exploit Cancer Drug Resistance

2020 ◽  
Vol 20 (9) ◽  
pp. 779-787
Author(s):  
Kajal Ghosal ◽  
Christian Agatemor ◽  
Richard I. Han ◽  
Amy T. Ku ◽  
Sabu Thomas ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Dna Repair ◽  
Fanconi Anemia ◽  
Cancer Drug ◽  
Drug Resistant ◽  
Cancer Drugs ◽  
Repair Pathway ◽  
Cancer Drug Resistance ◽  
Anti Cancer ◽  
Cancerous Cells

Chemotherapy employs anti-cancer drugs to stop the growth of cancerous cells, but one common obstacle to the success is the development of chemoresistance, which leads to failure of the previously effective anti-cancer drugs. Resistance arises from different mechanistic pathways, and in this critical review, we focus on the Fanconi Anemia (FA) pathway in chemoresistance. This pathway has yet to be intensively researched by mainstream cancer researchers. This review aims to inspire a new thrust toward the contribution of the FA pathway to drug resistance in cancer. We believe an indepth understanding of this pathway will open new frontiers to effectively treat drug-resistant cancer.

scholarly journals The SRS2 suppressor of rad6 mutations of Saccharomyces cerevisiae acts by channeling DNA lesions into the RAD52 DNA repair pathway.

Genetics ◽  
1990 ◽  
Vol 124 (4) ◽  
pp. 817-831 ◽  
Author(s):  
R H Schiestl ◽  
S Prakash ◽  
L Prakash
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Dna Repair ◽  
Gamma Ray ◽  
Dna Lesions ◽  
Recombinational Repair ◽  
Repair Pathway ◽  
Uv Mutagenesis ◽  
Uv Sensitivity ◽  
Suppressor Mutations ◽  
Induced Mutagenesis

Abstract rad6 mutants of Saccharomyces cerevisiae are defective in the repair of damaged DNA, DNA damage induced mutagenesis, and sporulation. In order to identify genes that can substitute for RAD6 function, we have isolated genomic suppressors of the UV sensitivity of rad6 deletion (rad6 delta) mutations and show that they also suppress the gamma-ray sensitivity but not the UV mutagenesis or sporulation defects of rad6. The suppressors show semidominance for suppression of UV sensitivity and dominance for suppression of gamma-ray sensitivity. The six suppressor mutations we isolated are all alleles of the same locus and are also allelic to a previously described suppressor of the rad6-1 nonsense mutation, SRS2. We show that suppression of rad6 delta is dependent on the RAD52 recombinational repair pathway since suppression is not observed in the rad6 delta SRS2 strain containing an additional mutation in either the RAD51, RAD52, RAD54, RAD55 or RAD57 genes. Possible mechanisms by which SRS2 may channel unrepaired DNA lesions into the RAD52 DNA repair pathway are discussed.

scholarly journals Rearrangements of the DNA in Carbon Ion-Induced Mutants of Arabidopsis thaliana

Genetics ◽  
2001 ◽  
Vol 157 (1) ◽  
pp. 379-387 ◽  
Author(s):  
Naoya Shikazono ◽  
Atsushi Tanaka ◽  
Hiroshi Watanabe ◽  
Shigemitsu Tano
Keyword(s):  
Arabidopsis Thaliana ◽  
Nonhomologous End Joining ◽  
Chromosome 3 ◽  
Chromosome 2 ◽  
Carbon Ions ◽  
Induced Mutations ◽  
End Joining ◽  
Carbon Ion ◽  
Induced Mutants ◽  
Dna Strand

Abstract To elucidate the nature of structural alterations in plants, three carbon ion-induced mutations in Arabidopsis thaliana, gl1-3, tt4(C1), and ttg1-21, were analyzed. The gl1-3 mutation was found to be generated by an inversion of a fragment that contained GL1 and Atpk7 loci on chromosome 3. The size of the inverted fragment was a few hundred kilobase pairs. The inversion was found to accompany an insertion of a 107-bp fragment derived from chromosome 2. The tt4(C1) mutation was also found to be due to an inversion. The size of the intervening region between the breakpoints was also estimated to be a few hundred kilobase pairs. In the case of ttg1-21, it was found that a break occurred at the TTG1 locus on chromosome 5, and reciprocal translocation took place between it and chromosome 3. From the sequences flanking the breakpoints, the DNA strand breaks induced by carbon ions were found to be rejoined using, if present, only short homologous sequences. Small deletions were also observed around the breakpoints. These results suggest that the nonhomologous end-joining (NHEJ) pathway operates after plant cells are exposed to ion particles.

scholarly journals MiR223-3p promotes synthetic lethality in BRCA1-deficient cancers

2019 ◽  
Vol 116 (35) ◽  
pp. 17438-17443 ◽  
Author(s):  
Gayathri Srinivasan ◽  
Elizabeth A. Williamson ◽  
Kimi Kong ◽  
Aruna S. Jaiswal ◽  
Guangcun Huang ◽  
...  
Keyword(s):  
Dna Repair ◽  
Cancer Cells ◽  
Synthetic Lethality ◽  
Negative Regulator ◽  
Nonhomologous End Joining ◽  
Chromosomal Translocations ◽  
Replication Forks ◽  
Repair Pathway ◽  
End Joining ◽  
Parp1 Inhibitors

Defects in DNA repair give rise to genomic instability, leading to neoplasia. Cancer cells defective in one DNA repair pathway can become reliant on remaining repair pathways for survival and proliferation. This attribute of cancer cells can be exploited therapeutically, by inhibiting the remaining repair pathway, a process termed synthetic lethality. This process underlies the mechanism of the Poly-ADP ribose polymerase-1 (PARP1) inhibitors in clinical use, which target BRCA1 deficient cancers, which is indispensable for homologous recombination (HR) DNA repair. HR is the major repair pathway for stressed replication forks, but when BRCA1 is deficient, stressed forks are repaired by back-up pathways such as alternative nonhomologous end-joining (aNHEJ). Unlike HR, aNHEJ is nonconservative, and can mediate chromosomal translocations. In this study we have found that miR223-3p decreases expression of PARP1, CtIP, and Pso4, each of which are aNHEJ components. In most cells, high levels of microRNA (miR) 223–3p repress aNHEJ, decreasing the risk of chromosomal translocations. Deletion of the miR223 locus in mice increases PARP1 levels in hematopoietic cells and enhances their risk of unprovoked chromosomal translocations. We also discovered that cancer cells deficient in BRCA1 or its obligate partner BRCA1-Associated Protein-1 (BAP1) routinely repress miR223-3p to permit repair of stressed replication forks via aNHEJ. Reconstituting the expression of miR223-3p in BRCA1- and BAP1-deficient cancer cells results in reduced repair of stressed replication forks and synthetic lethality. Thus, miR223-3p is a negative regulator of the aNHEJ DNA repair and represents a therapeutic pathway for BRCA1- or BAP1-deficient cancers.

An exonuclease I-sensitive DNA repair pathway in Deinococcus radiodurans: a major determinant of radiation resistance

2006 ◽  
Vol 59 (4) ◽  
pp. 1308-1316 ◽  
Author(s):  
Hari S. Misra ◽  
Nivedita P. Khairnar ◽  
Swathi Kota ◽  
Smriti Shrivastava ◽  
Vasudha P. Joshi ◽  
...  
Keyword(s):  
Dna Repair ◽  
Radiation Resistance ◽  
Deinococcus Radiodurans ◽  
Major Determinant ◽  
Repair Pathway ◽  
Exonuclease I

scholarly journals Different effects of carbon ion beams and X-rays on clonogenic survival and DNA repair in human pancreatic cancer stem-like cells

2012 ◽  
Vol 105 (2) ◽  
pp. 258-265 ◽  
Author(s):  
Kazuhiko Oonishi ◽  
Xing Cui ◽  
Hirokazu Hirakawa ◽  
Akira Fujimori ◽  
Takehiko Kamijo ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Dna Repair ◽  
Clonogenic Survival ◽  
Ion Beams ◽  
Human Pancreatic Cancer ◽  
X Rays ◽  
Carbon Ion

Genetic variation in the DNA repair pathway as a potential determinant of response to platinum-based chemotherapy in breast cancer

2017 ◽  
Vol 233 (4) ◽  
pp. 2752-2758 ◽  
Author(s):  
Farimah Beheshti ◽  
Seyed Mahdi Hassanian ◽  
Majid Khazaei ◽  
Mahmoud Hosseini ◽  
Soodabeh ShahidSales ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Repair ◽  
Genetic Variation ◽  
Repair Pathway ◽  
Platinum Based Chemotherapy ◽  
Potential Determinant

Immunotherapy in combination with PARP inhibition in advanced cervical cancer patients functionally competent or deficient for the Fanconi anemia repair pathway.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS5597-TPS5597
Author(s):  
John Paul Diaz ◽  
Wenrui Duan ◽  
Eric Schroeder ◽  
Zuanel Diaz ◽  
Nicholas Lambrou ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cell Death ◽  
Dna Repair ◽  
Programmed Cell Death ◽  
Phase Ii ◽  
Fanconi Anemia ◽  
Objective Response ◽  
Repair Pathway ◽  
Mutational Burden ◽  
Tumor Mutational Burden

TPS5597 Background: Immunotherapy has improved outcomes for patients with recurrent or metastatic cervical cancer whose tumors express PD-L1. Pembrolizumab (PEM), a monoclonal antibody that binds to programmed cell death 1 (PD 1) receptor, inhibits interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2). It is approved for the treatment of recurrent or metastatic cervical cancer. Despite promising results, new strategies are being developed to improve immunotherapy responses. This includes DNA-damaging agents that have the potential to enhance the response to immunotherapy by promoting neo-antigen release, increasing tumor mutational burden, and enhancing PD-L1 expression. Poly-ADP-ribose polymerase (PARP) inhibitors, such as olaparib, have shown synergy with immunotherapy in preclinical and early clinical studies. PARP-based therapy is based on the inhibition of single-strand DNA repair, leading to DNA damage and increased tumor mutational burden. As a result, the tumor becomes a more attractive target for immunotherapy. Based on this, we are investigating the interplay between homologous recombination (HR) repair deficiency, another mechanism of DNA repair, and solid tumor response to ICI. Our approach uses an all-inclusive functional immunofluorescence assay of the Fanconi Anemia triple-staining immunofluorescence (FATSI) we developed and can be performed in paraffin-embedded tumors. Methods: This is a phase II open-label single center trial evaluating the role of PEM and olaparib in patients with metastatic cervical cancer who have progressed on first-line standard of care chemotherapy. FATSI will be performed in all patients. We hypothesize that FATSI negative tumors will be associated with improved responses. Other eligibility criteria include measurable disease by imaging, 18 years of age or older, and no previous exposure to ICI or PARP inhibitor. The primary objective is to evaluate the immune-related objective response rate (iORR) achieved in patients with FA Repair Pathway functionally competent and functionally deficient tumors. Secondary objectives include 20-week progression free survival and overall survival. Other exploratory objectives include evaluation of the mutation load and markers of neo-antigenicity, T cell receptor clonotype analyses (before and after treatment), and alterations in HR repair genes. We will utilize a two-stage phase II design to detect an iORR ≥ 20% in the whole population tested vs. the null hypothesis that the true iORR ≤5%, represents a response by chance alone or other infrequent unknown mechanisms. An interim analysis requires at least 2 of the first 20 evaluable patients enrolled have an objective response. If this occurs, we will accrue 28 additional patients to total 48. Enrollment is ongoing and two patients are currently on treatment. Clinical trial information: NCT04483544.

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