Gene Repair: Past, Present, and Future

2016 ◽  
pp. 410-425
Keyword(s):  
Gene Repair

Repair pathway choice for double-strand breaks

2020 ◽  
Vol 64 (5) ◽  
pp. 765-777 ◽  
Author(s):  
Yixi Xu ◽  
Dongyi Xu
Keyword(s):  
Cell Cycle ◽  
Double Strand Breaks ◽  
Homologous Region ◽  
Gene Repair ◽  
Repair Pathway ◽  
Dna Double Strand Breaks ◽  
Environmental Radiation ◽  
Strand Breaks ◽  
Dna End Resection ◽  
End Resection

Abstract Deoxyribonucleic acid (DNA) is at a constant risk of damage from endogenous substances, environmental radiation, and chemical stressors. DNA double-strand breaks (DSBs) pose a significant threat to genomic integrity and cell survival. There are two major pathways for DSB repair: nonhomologous end-joining (NHEJ) and homologous recombination (HR). The extent of DNA end resection, which determines the length of the 3′ single-stranded DNA (ssDNA) overhang, is the primary factor that determines whether repair is carried out via NHEJ or HR. NHEJ, which does not require a 3′ ssDNA tail, occurs throughout the cell cycle. 53BP1 and the cofactors PTIP or RIF1-shieldin protect the broken DNA end, inhibit long-range end resection and thus promote NHEJ. In contrast, HR mainly occurs during the S/G2 phase and requires DNA end processing to create a 3′ tail that can invade a homologous region, ensuring faithful gene repair. BRCA1 and the cofactors CtIP, EXO1, BLM/DNA2, and the MRE11–RAD50–NBS1 (MRN) complex promote DNA end resection and thus HR. DNA resection is influenced by the cell cycle, the chromatin environment, and the complexity of the DNA end break. Herein, we summarize the key factors involved in repair pathway selection for DSBs and discuss recent related publications.

scholarly journals Strand Bias in Targeted Gene Repair Is Influenced by Transcriptional Activity

2002 ◽  
Vol 22 (11) ◽  
pp. 3852-3863 ◽  
Author(s):  
Li Liu ◽  
Michael C. Rice ◽  
Miya Drury ◽  
Shuqiu Cheng ◽  
Howard Gamper ◽  
...  
Keyword(s):  
Transcriptional Activity ◽  
Fluorescent Protein ◽  
Fusion Gene ◽  
Strand Bias ◽  
Nucleotide Exchange ◽  
Gene Repair ◽  
Protein Fusion ◽  
Template Strand ◽  
Targeted Gene Repair ◽  
Targeting Vector

ABSTRACT Modified single-stranded DNA oligonucleotides can direct nucleotide exchange in Saccharomyces cerevisiae. Point and frameshift mutations are corrected in a reaction catalyzed by cellular enzymes involved in various DNA repair processes. The present model centers on the annealing of the vector to one strand of the helix, followed by the correction of the designated base. The choice of which strand to target is a reaction parameter that can be controlled, so here we investigate the properties of strand bias in targeted gene repair. An in vivo system has been established in which a plasmid containing an actively transcribed, but mutated, hygromycin-enhanced green fluorescent protein fusion gene is targeted for repair and upon conversion will confer hygromycin resistance on the cell. Overall transcriptional activity has a positive influence on the reaction, elevating the frequency. If the targeting vector is synthesized so that it directs nucleotide repair on the nontranscribed strand, the level of gene repair is higher than if the template strand is targeted. We provide data showing that the targeting vector can be displaced from the template strand by an active T7 phage RNA polymerase. The strand bias is not influenced by which strand serves as the leading or lagging strand during DNA synthesis. These results may provide an explanation for the enhancement of gene repair observed when the nontemplate strand is targeted.

Construction of Adoxophyes honmai nucleopolyhedrovirus bacmid DNA by using a gene-repair BAC cassette

2015 ◽  
Vol 50 (1) ◽  
pp. 143-146
Author(s):  
Yasumasa Saito ◽  
Yasuhisa Kunimi ◽  
Madoka Nakai
Keyword(s):  
Gene Repair ◽  
Adoxophyes Honmai

scholarly journals Gene repair tool for stem cells

Nature ◽  
2011 ◽  
Vol 474 (7349) ◽  
pp. 8-8
Keyword(s):  
Stem Cells ◽  
Gene Repair

Sickle Cell Disease Hematopoietic Stem Cell gene therapy with globin gene addition is promising

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Gene Therapy ◽  
Stem Cell ◽  
Sickle Cell Disease ◽  
Hematopoietic Stem Cell ◽  
Sickle Cell ◽  
Globin Gene ◽  
Autologous Transplantation ◽  
Gene Repair ◽  
Cell Disease ◽  
Hematopoietic Stem

Autologous transplantation of gene-modified HSCs might be used to treat Sickle Cell Disease (SCD) once and for all. Hematopoietic Stem Cell (HSC) gene therapy with lentiviral-globin gene addition was optimized by HSC collection, vector constructs, lentiviral transduction, and conditioning in the current gene therapy experiment for SCD, resulting in higher gene marking and phenotypic correction. Further advancements over the next decade should allow for a widely approved gene-addition therapy. Long-term engraftment is crucial for gene-corrected CD34+ HSCs, which might be addressed in the coming years, and gene repair of the SCD mutation in the-globin gene can be achieved in vitro using genome editing in CD34+ cells. Because of breakthroughs in efficacy, safety, and delivery strategies, in vivo gene addition and gene correction in BM HSCs is advancing. Overall, further research is needed, but HSC-targeted gene addition/gene editing therapy is a promising SCD therapy with curative potential that might be widely available soon.

scholarly journals Environmental pollutants-dependent molecular pathways and carcinogenesis

Biodiscovery ◽  
2019 ◽  
Vol 22 ◽  
Author(s):  
Myriam El Helou ◽  
Pascale A. Cohen ◽  
Mona Diab-Assaf ◽  
Sandra Ghayad
Keyword(s):  
Gene Expression ◽  
Environmental Pollutants ◽  
Environmental Chemicals ◽  
Gene Repair ◽  
Hormone Production ◽  
Aryl Hydrocarbon ◽  
Repair Mechanisms ◽  
Cellular Signal ◽  
And Function ◽  
G Protein Coupled

Exposure to environmental pollutants can modulate many biological and molecular processes such as gene expression, gene repair mechanisms, hormone production and function and inflammation, resulting in adverse effects on human health including the occurrence and development of different types of cancer. Carcinogenesis is a complex and long process, taking place in multiple stages and is affected by multiple factors. Some environmental molecules are genotoxic, able to damage the DNA or to induce mutations and changes in gene expression acting as initiators of carcinogenesis. Other molecules called xenoestrogens can promote carcinogenesis by their mitogenic effects by possessing estrogenic-like activities and consequently acting as endocrine disruptors causing multiple alterations in cellular signal transduction pathways. In this review, we focus on recent research on environmental chemicals-driven molecular functions in human cancers. For this purpose, we will be discussing the case of two receptors in mediating environmental pollutants effects: the established nuclear receptor, the Aryl hydrocarbon receptor (AhR) and the emerging membrane receptor, G-protein coupled estrogen receptor 1 (GPER1).

scholarly journals Eliminating SCID row: new approaches to SCID

Hematology ◽  
2014 ◽  
Vol 2014 (1) ◽  
pp. 475-480 ◽  
Author(s):  
Donald B. Kohn
Keyword(s):  
Gene Therapy ◽  
Stem Cell ◽  
Ex Vivo ◽  
Autologous Transplantation ◽  
Unrelated Donor ◽  
Primary Immune Deficiency ◽  
Gene Repair ◽  
Gene Correction ◽  
Hematopoietic Stem ◽  
New Approaches

Abstract Treatments for patients with SCID by hematopoietic stem cell transplantation (HSCT) have changed this otherwise lethal primary immune deficiency disorder into one with an increasingly good prognosis. SCID has been the paradigm disorder supporting many key advances in the field of HSCT, with first-in-human successes with matched sibling, haploidentical, and matched unrelated donor allogeneic transplantations. Nevertheless, the optimal approaches for HSCT are still being defined, including determining the optimal stem cell sources, the use and types of pretransplantation conditioning, and applications for SCID subtypes associated with radiosensitivity, for patients with active viral infections and for neonates. Alternatively, autologous transplantation after ex vivo gene correction (gene therapy) has been applied successfully to the treatment of adenosine deaminase–deficient SCID and X-linked SCID by vector-mediated gene addition. Gene therapy holds the prospect of avoiding risks of GVHD and would allow each patient to be their own donor. New approaches to gene therapy by gene correction in autologous HSCs using site-specific endonuclease-mediated homology-driven gene repair are under development. With newborn screening becoming more widely adopted to detect SCID patients before they develop complications, the prognosis for SCID is expected to improve further. This chapter reviews recent advances and ongoing controversies in allogeneic and autologous HSCT for SCID.

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