scholarly journals Testing the retroelement invasion hypothesis for the emergence of the ancestral eukaryotic cell

2018 ◽  
Vol 115 (49) ◽  
pp. 12465-12470 ◽  
Author(s):  
Gloria Lee ◽  
Nicholas A. Sherer ◽  
Neil H. Kim ◽  
Ema Rajic ◽  
Davneet Kaur ◽  
...  
Keyword(s):  
Dna Repair ◽  
Group Ii Intron ◽  
Eukaryotic Cell ◽  
Nonhomologous End Joining ◽  
Bacterial Group ◽  
End Joining ◽  
Simple Cells ◽  
Evolutionary Consequence ◽  
Human Line ◽  
Copy And Paste

Phylogenetic evidence suggests that the invasion and proliferation of retroelements, selfish mobile genetic elements that copy and paste themselves within a host genome, was one of the early evolutionary events in the emergence of eukaryotes. Here we test the effects of this event by determining the pressures retroelements exert on simple genomes. We transferred two retroelements, human LINE-1 and the bacterial group II intron Ll.LtrB, into bacteria, and find that both are functional and detrimental to growth. We find, surprisingly, that retroelement lethality and proliferation are enhanced by the ability to perform eukaryotic-like nonhomologous end-joining (NHEJ) DNA repair. We show that the only stable evolutionary consequence in simple cells is maintenance of retroelements in low numbers, suggesting how retrotransposition rates and costs in early eukaryotes could have been constrained to allow proliferation. Our results suggest that the interplay between NHEJ and retroelements may have played a fundamental and previously unappreciated role in facilitating the proliferation of retroelements, elements of which became the ancestors of the spliceosome components in eukaryotes.

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.

scholarly journals Role of DNA Repair by Nonhomologous-End Joining in Bacillus subtilis Spore Resistance to Extreme Dryness, Mono- and Polychromatic UV, and Ionizing Radiation

2007 ◽  
Vol 189 (8) ◽  
pp. 3306-3311 ◽  
Author(s):  
Ralf Moeller ◽  
Erko Stackebrandt ◽  
Günther Reitz ◽  
Thomas Berger ◽  
Petra Rettberg ◽  
...  
Keyword(s):  
Dna Repair ◽  
Bacillus Subtilis ◽  
Ionizing Radiation ◽  
Ultrahigh Vacuum ◽  
Nonhomologous End Joining ◽  
Wild Type ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Spore Resistance

ABSTRACT The role of DNA repair by nonhomologous-end joining (NHEJ) in spore resistance to UV, ionizing radiation, and ultrahigh vacuum was studied in wild-type and DNA repair mutants (recA, splB, ykoU, ykoV, and ykoU ykoV mutants) of Bacillus subtilis. NHEJ-defective spores with mutations in ykoU, ykoV, and ykoU ykoV were significantly more sensitive to UV, ionizing radiation, and ultrahigh vacuum than wild-type spores, indicating that NHEJ provides an important pathway during spore germination for repair of DNA double-strand breaks.

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 DNA repair of myeloma plasma cells correlates with clinical outcome: the effect of the nonhomologous end-joining inhibitor SCR7

Blood ◽  
2016 ◽  
Vol 128 (9) ◽  
pp. 1214-1225 ◽  
Author(s):  
Maria Gkotzamanidou ◽  
Evangelos Terpos ◽  
Christina Bamia ◽  
Nikhil C. Munshi ◽  
Meletios A. Dimopoulos ◽  
...  
Keyword(s):  
Dna Repair ◽  
Clinical Outcome ◽  
Plasma Cells ◽  
Nonhomologous End Joining ◽  
End Joining ◽  
Key Points

Key Points Responders to melphalan therapy are characterized by slower rates of NER and DSB/R mechanisms and higher apoptotic rates. The DSB/R inhibitor SCR7 enhances cytotoxicity of melphalan against myeloma plasma cells.

scholarly journals The C-Terminal Domain of Cernunnos/XLF Is Dispensable for DNA Repair In Vivo

2008 ◽  
Vol 29 (5) ◽  
pp. 1116-1122 ◽  
Author(s):  
Laurent Malivert ◽  
Isabelle Callebaut ◽  
Paola Rivera-Munoz ◽  
Alain Fischer ◽  
Jean-Paul Mornon ◽  
...  
Keyword(s):  
Dna Repair ◽  
Nonhomologous End Joining ◽  
Dna Ligase ◽  
Repair Pathway ◽  
End Joining ◽  
Functional Assays ◽  
The Core ◽  
Ligase Iv

ABSTRACT The core nonhomologous end-joining DNA repair pathway is composed of seven factors: Ku70, Ku80, DNA-PKcs, Artemis, XRCC4 (X4), DNA ligase IV (L4), and Cernunnos/XLF (Cernunnos). Although Cernunnos and X4 are structurally related and participate in the same complex together with L4, they have distinct functions during DNA repair. L4 relies on X4 but not on Cernunnos for its stability, and L4 is required for optimal interaction of Cernunnos with X4. We demonstrate here, using in vitro-generated Cernunnos mutants and a series of functional assays in vivo, that the C-terminal region of Cernunnos is dispensable for its activity during DNA repair.

scholarly journals Loss of autophagy causes a synthetic lethal deficiency in DNA repair

2015 ◽  
Vol 112 (3) ◽  
pp. 773-778 ◽  
Author(s):  
Emma Y. Liu ◽  
Naihan Xu ◽  
Jim O’Prey ◽  
Laurence Y. Lao ◽  
Sanket Joshi ◽  
...  
Keyword(s):  
Dna Repair ◽  
Repair Process ◽  
Double Strand Breaks ◽  
Nonhomologous End Joining ◽  
Cytoplasmic Process ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Synthetic Lethal ◽  
Strand Breaks ◽  
Genomic Damage

(Macro)autophagy delivers cellular constituents to lysosomes for degradation. Although a cytoplasmic process, autophagy-deficient cells accumulate genomic damage, but an explanation for this effect is currently unclear. We report here that inhibition of autophagy causes elevated proteasomal activity leading to enhanced degradation of checkpoint kinase 1 (Chk1), a pivotal factor for the error-free DNA repair process, homologous recombination (HR). We show that loss of autophagy critically impairs HR and that autophagy-deficient cells accrue micronuclei and sub-G1 DNA, indicators of diminished genomic integrity. Moreover, due to impaired HR, autophagy-deficient cells are hyperdependent on nonhomologous end joining (NHEJ) for repair of DNA double-strand breaks. Consequently, inhibition of NHEJ following DNA damage in the absence of autophagy results in persistence of genomic lesions and rapid cell death. Because autophagy deficiency occurs in several diseases, these findings constitute an important link between autophagy and DNA repair and highlight a synthetic lethal strategy to kill autophagy-deficient cells.

scholarly journals Preventing Nonhomologous End Joining Suppresses DNA Repair Defects of Fanconi Anemia

2010 ◽  
Vol 39 (1) ◽  
pp. 25-35 ◽  
Author(s):  
Adele Adamo ◽  
Spencer J. Collis ◽  
Carrie A. Adelman ◽  
Nicola Silva ◽  
Zuzana Horejsi ◽  
...  
Keyword(s):  
Dna Repair ◽  
Fanconi Anemia ◽  
Nonhomologous End Joining ◽  
End Joining
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