Effects of Radiation Quality and Oxygen on Clustered DNA Lesions and Cell Death

2011 ◽  
Vol 176 (5) ◽  
pp. 587-602 ◽  
Author(s):  
Robert D. Stewart ◽  
Victor K. Yu ◽  
Alexandros G. Georgakilas ◽  
Constantinos Koumenis ◽  
Joo Han Park ◽  
...  
Keyword(s):  
Cell Death ◽  
Dna Lesions ◽  
Radiation Quality ◽  
Effects Of Radiation

scholarly journals Glutathione Depletion and Carbon Ion Radiation Potentiate Clustered DNA Lesions, Cell Death and Prevent Chromosomal Changes in Cancer Cells Progeny

PLoS ONE ◽  
2012 ◽  
Vol 7 (11) ◽  
pp. e44367 ◽  
Author(s):  
Maïté Hanot ◽  
Anthony Boivin ◽  
Céline Malésys ◽  
Michaël Beuve ◽  
Anthony Colliaux ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Dna Lesions ◽  
Glutathione Depletion ◽  
Carbon Ion ◽  
Chromosomal Changes

scholarly journals Disuccinyl Betulin Triggers Metacaspase-Dependent Endonuclease G-Mediated Cell Death in Unicellular Protozoan Parasite Leishmania donovani

2014 ◽  
Vol 58 (4) ◽  
pp. 2186-2201 ◽  
Author(s):  
Sayan Chowdhury ◽  
Tulika Mukherjee ◽  
Somenath Roy Chowdhury ◽  
Souvik Sengupta ◽  
Sibabrata Mukhopadhyay ◽  
...  
Keyword(s):  
Cell Death ◽  
Leishmania Donovani ◽  
Protozoan Parasite ◽  
Degradation Process ◽  
Dna Lesions ◽  
Death Process ◽  
Unicellular Organism ◽  
Content Type ◽  
Atp Production ◽  
Endonuclease G

ABSTRACTThe unicellular organismLeishmaniaundergoes apoptosis-like cell death in response to external stress or exposure to antileishmanial agents. Here, we showed that 3-O,28-O-disuccinyl betulin (DiSB), a potent topoisomerase type IB inhibitor, induced parasitic cell death by generating oxidative stress. The characteristic feature of the death process resembled the programmed cell death (PCD) seen in higher eukaryotes. In the current study, the generation of reactive oxygen species (ROS), followed by the depolarization of mitochondrial membrane potential (ΔΨm), caused a loss in ATP production inLeishmaniaparasites. This further gave positive feedback to produce a large amount of ROS, which in turn caused oxidative DNA lesions and genomic DNA fragmentation. The treatment of promastigotes with DiSB induced high expression levels of metacaspase protein that led to cell death in this unicellular organism. The PCD was insensitive to benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD-fmk), suggesting that the death process was not associated with the activation of caspases. DiSB treatment translocatedLeishmania donovaniendonuclease G (LdEndoG) from mitochondria to the nucleus, which was responsible for the DNA degradation process. Conditional antisense knockdown ofL. donovanimetacaspase (LdMC), as well as EndoG, -subverted death of the parasite and rescued cell cycle arrest in G1phase. The present study on the effector molecules associated with the PCD pathway of the parasite should help to manifest the mechanisms of PCD and also might be exploited in antileishmanial chemotherapy.

scholarly journals The 89-kDa PARP1 cleavage fragment serves as a cytoplasmic PAR carrier to induce AIF-mediated apoptosis

2020 ◽  
pp. jbc.RA120.014479
Author(s):  
Masato Mashimo ◽  
Mayu Onishi ◽  
Arina Uno ◽  
Akari Tanimichi ◽  
Akari Nobeyama ◽  
...  
Keyword(s):  
Cell Death ◽  
Dna Repair ◽  
Programmed Cell Death ◽  
Nuclear Protein ◽  
Current Knowledge ◽  
Dna Lesions ◽  
Caspase Cleavage ◽  
Cytoplasmic Proteins ◽  
Localization Signal ◽  
Apoptosis Inducing Factor

Poly(ADP-ribose) polymerase (PARP1) is a nuclear protein that is activated by binding to DNA lesions and catalyzes poly(ADP- ribosyl)ation of nuclear acceptor proteins, including PARP1 itself, to recruit DNA repair machinery to DNA lesions. When excessive DNA damage occurs, poly(ADP-ribose) (PAR) produced by PARP1 is translocated to the cytoplasm, changing the activity and localization of cytoplasmic proteins e.g. apoptosis-inducing factor (AIF), hexokinase and resulting in cell death. This cascade, termed parthanatos, is a caspase-independent programmed cell death distinct from necrosis and apoptosis. In contrast, PARP1 is a substrate of activated caspases 3 and 7 in caspase-dependent apoptosis. Once cleaved, PARP1 loses its activity, thereby suppressing DNA repair. Caspase cleavage of PARP1 occurs within a nuclear localization signal near the DNA-binding domain, resulting in the formation of 24-kDa and 89-kDa fragments. In the current study, we found that caspase activation by staurosporine- and actinomycin D-induced PARP1 auto-poly(ADP-ribosyl)ation and fragmentation, generating poly(ADP-ribosyl)ated 89-kDa and 24-kDa PARP1 fragments. The 89-kDa PARP1 fragments with covalently attached PAR polymers were translocated to the cytoplasm, while 24-kDa fragments remained associated with DNA lesions. In the cytoplasm, AIF binding to PAR attached to the 89-kDa PARP1 fragment facilitated its translocation to the nucleus. Thus, the 89-kDa PARP1 fragment is a PAR carrier to the cytoplasm, inducing AIF release from mitochondria. Elucidation of the caspase-mediated interaction between apoptosis and parthanatos pathways extend the current knowledge on mechanisms underlying programmed cell death and may lead to new therapeutic targets.

scholarly journals Involvement of RAD9-Dependent Damage Checkpoint Control in Arrest of Cell Cycle, Induction of Cell Death, and Chromosome Instability Caused by Defects in Origin Recognition Complex in Saccharomyces cerevisiae

2002 ◽  
Vol 1 (2) ◽  
pp. 200-212 ◽  
Author(s):  
Keiichi Watanabe ◽  
Jun Morishita ◽  
Keiko Umezu ◽  
Katsuhiko Shirahige ◽  
Hisaji Maki
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Origin Recognition Complex ◽  
Chromosome Instability ◽  
Dna Lesions ◽  
Checkpoint Control ◽  
Origin Firing ◽  
Prolonged Incubation ◽  
Diploid Cells ◽  
Origin Recognition

ABSTRACT Perturbation of origin firing in chromosome replication is a possible cause of spontaneous chromosome instability in multireplicon organisms. Here, we show that chromosomal abnormalities, including aneuploidy and chromosome rearrangement, were significantly increased in yeast diploid cells with defects in the origin recognition complex. The cell cycle of orc1-4/orc1-4 temperature-sensitive mutant was arrested at the G2/M boundary, after several rounds of cell division at the restrictive temperature. However, prolonged incubation of the mutant cells at 37°C led to abrogation of G2 arrest, and simultaneously the cells started to lose viability. A sharp increase in chromosome instability followed the abrogation of G2 arrest. In orc1-4/orc1-4 rad9Δ/rad9Δ diploid cells grown at 37°C, G2 arrest and induction of cell death were suppressed, while chromosome instability was synergistically augmented. These findings indicated that DNA lesions caused by a defect in Orc1p function trigger the RAD9-dependent checkpoint control, which ensures genomic integrity either by stopping the cell cycle progress until lesion repair, or by inducing cell death when the lesion is not properly repaired. At semirestrictive temperatures, orc2-1/orc2-1 diploid cells demonstrated G2 arrest and loss of cell viability, both of which require RAD9-dependent checkpoint control. However, chromosome instability was not induced in orc2-1/orc2-1 cells, even in the absence of the checkpoint control. These data suggest that once cells lose the damage checkpoint control, perturbation of origin firing can be tolerated by the cells. Furthermore, although a reduction in origin-firing capacity does not necessarily initiate chromosome instability, the Orc1p possesses a unique function, the loss of which induces instability in the chromosome.

Sign in / Sign up

Export Citation Format

Share Document