Alsterpaullone, a novel cyclin-dependent kinase inhibitor, induces apoptosis by activation of caspase-9 due to perturbation in mitochondrial membrane potential

2003 ◽  
Vol 36 (4) ◽  
pp. 183-194 ◽  
Author(s):  
Tyler Lahusen ◽  
Adriana De Siervi ◽  
Conrad Kunick ◽  
Adrian M. Senderowicz
Keyword(s):  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Kinase Inhibitor ◽  
Cyclin Dependent Kinase ◽  
Caspase 9 ◽  
Cyclin Dependent Kinase Inhibitor

scholarly journals The Short Isoform of DNAJB6 Protects against 1-Methyl-4-phenylpridinium Ion-Induced Apoptosis in LN18 Cells via Inhibiting Both ROS Formation and Mitochondrial Membrane Potential Loss

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Yeon-Mi Hong ◽  
Yohan Hong ◽  
Yeong-Gon Choi ◽  
Sujung Yeo ◽  
Soo Hee Jin ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Molecular Mechanisms ◽  
Mitochondrial Pathway ◽  
Caspase 9 ◽  
Ros Formation ◽  
Mitochondrial Membrane Potential Loss ◽  
Induced Apoptosis ◽  
Shock Proteins

In a previous study, we found that the short isoform of DNAJB6 (DNAJB6(S)) had been decreased in the striatum of a mouse model of Parkinson’s disease (PD) induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). DNAJB6, one of the heat shock proteins, has been implicated in the pathogenesis of PD. In this study, we explored the cytoprotective effect of DNAJB6(S) against 1-methyl-4-phenylpyridinium ion- (MPP+-) induced apoptosis and the underlying molecular mechanisms in cultured LN18 cells from astrocytic tumors. We observed that MPP+ significantly reduced the cell viability and induced apoptosis in LN18 glioblastoma cells. DNAJB6(S) protected LN18 cells against MPP+-induced apoptosis not only by suppressing Bax cleavage but also by inhibiting a series of apoptotic events including loss of mitochondrial membrane potential, increase in intracellular reactive oxygen species, and activation of caspase-9. These observations suggest that the cytoprotective effects of DNAJB6(S) may be mediated, at least in part, by the mitochondrial pathway of apoptosis.

scholarly journals Apaf-1, Bcl-xL, Cytochrome c, and Caspase-9 Form the Critical Elements for Cerebral Vascular Protection by Erythropoietin

2003 ◽  
Vol 23 (3) ◽  
pp. 320-330 ◽  
Author(s):  
Zhao Zhong Chong ◽  
Jing-Qiong Kang ◽  
Kenneth Maiese
Keyword(s):  
Membrane Potential ◽  
Cytochrome C ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Cell Injury ◽  
Vascular System ◽  
Dna Integrity ◽  
Vascular Protection ◽  
Caspase 9 ◽  
Cerebral Vascular

Erythropoietin (EPO) plays a prominent role in the regulation of the hematopoietic system, but the potential function of this trophic factor as a cytoprotectant in the cerebral vascular system is not known. The authors examined the ability of EPO to modulate a series of death-related cellular pathways during free radical–induced injury in cerebral microvascular endothelial cells (ECs). Endothelial cell injury was evaluated by trypan blue, DNA fragmentation, membrane phosphatidylserine exposure, apoptotic protease–activating factor-1 (Apaf-1), and Bcl-xL expression, mitochondrial membrane potential, cytochrome c release, and cysteine protease activity. They show that constitutive EPO is present in ECs but is insufficient to prevent cellular injury. Signaling through the EPO receptor, however, remains biologically responsive to exogenous EPO administration to offer significant protection against nitric oxide–induced injury. Exogenous EPO maintains both genomic DNA integrity and cellular membrane asymmetry through parallel pathways that prevent the induction of Apaf-1 and preserve mitochondrial membrane potential in conjunction with enhanced Bcl-xL expression. Consistent with the modulation of Apaf-1 and the release of cytochrome c, EPO also inhibits the activation of caspase-9 and caspase-3–like activities. Identification of novel cytoprotective pathways used by EPO may serve as therapeutic targets for cerebral vascular disease.

scholarly journals Caspase Inhibition Extends the Commitment to Neuronal Death Beyond Cytochrome c Release to the Point of Mitochondrial Depolarization

2000 ◽  
Vol 150 (1) ◽  
pp. 131-144 ◽  
Author(s):  
Mohanish Deshmukh ◽  
Keisuke Kuida ◽  
Eugene M. Johnson
Keyword(s):  
Membrane Potential ◽  
Cytochrome C ◽  
Mitochondrial Membrane Potential ◽  
Neuronal Death ◽  
Mitochondrial Membrane ◽  
Sympathetic Neurons ◽  
Caspase Inhibitor ◽  
Caspase 9 ◽  
Cytochrome C Release ◽  
Caspase Inhibition

Nerve growth factor (NGF) deprivation induces a Bax-dependent, caspase-dependent programmed cell death in sympathetic neurons. We examined whether the release of cytochrome c was accompanied by the loss of mitochondrial membrane potential during sympathetic neuronal death. NGF- deprived, caspase inhibitor–treated mouse sympathetic neurons maintained mitochondrial membrane poten-tial for 25–30 h after releasing cytochrome c. NGF- deprived sympathetic neurons became committed to die, as measured by the inability of cells to be rescued by NGF readdition, at the time of cytochrome c release. In the presence of caspase inhibitor, however, this commitment to death was extended beyond the point of cytochrome c release, but only up to the subsequent point of mitochondrial membrane potential loss. Caspase-9 deficiency also arrested NGF-deprived sympathetic neurons after release of cytochrome c, and permitted these neurons to be rescued with NGF readdition. Commitment to death in the NGF-deprived, caspase- 9–deficient sympathetic neurons was also coincident with the loss of mitochondrial membrane potential. Thus, caspase inhibition extended commitment to death in trophic factor–deprived sympathetic neurons and allowed recovery of neurons arrested after the loss of cytochrome c, but not beyond the subsequent loss of mitochondrial membrane potential.

scholarly journals Cytotoxic Mechanism of Sphaerodactylomelol, an Uncommon Bromoditerpene Isolated from Sphaerococcus coronopifolius

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1374
Author(s):  
Celso Alves ◽  
Joana Silva ◽  
Susete Pinteus ◽  
Eva Alonso ◽  
Rebeca Alvariño ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Anticancer Agents ◽  
Mitochondrial Membrane ◽  
Malignant Cell ◽  
Breast Adenocarcinoma ◽  
H2o2 Production ◽  
Caspase 9 ◽  
Chemical Structures ◽  
Mcf 7

Marine natural products have exhibited uncommon chemical structures with relevant antitumor properties highlighting their potential to inspire the development of new anticancer agents. The goal of this work was to study the antitumor activities of the brominated diterpene sphaerodactylomelol, a rare example of the dactylomelane family. Cytotoxicity (10–100 µM; 24 h) was evaluated on tumor cells (A549, CACO-2, HCT-15, MCF-7, NCI-H226, PC-3, SH-SY5Y, SK-ML-28) and the effects estimated by MTT assay. Hydrogen peroxide (H2O2) levels and apoptosis biomarkers (membrane translocation of phosphatidylserine, depolarization of mitochondrial membrane potential, Caspase-9 activity, and DNA condensation and/or fragmentation) were studied in the breast adenocarcinoma cellular model (MCF-7) and its genotoxicity on mouse fibroblasts (L929). Sphaerodactylomelol displayed an IC50 range between 33.04 and 89.41 µM without selective activity for a specific tumor tissue. The cells’ viability decrease was accompanied by an increase on H2O2 production, a depolarization of mitochondrial membrane potential and an increase of Caspase-9 activity and DNA fragmentation. However, the DNA damage studies in L929 non-malignant cell line suggested that this compound is not genotoxic for normal fibroblasts. Overall, the results suggest that the cytotoxicity of sphaerodactylomelol seems to be mediated by an increase of H2O2 levels and downstream apoptosis.

scholarly journals Ligands of the Mitochondrial 18 kDa Translocator Protein Attenuate Apoptosis of Human Glioblastoma Cells Exposed to Erucylphosphohomocholine

2008 ◽  
Vol 30 (5) ◽  
pp. 435-450
Author(s):  
Wilfried Kugler ◽  
Leo Veenman ◽  
Yulia Shandalov ◽  
Svetlana Leschiner ◽  
Ilana Spanier ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Cytochrome C ◽  
Cyclosporin A ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Translocator Protein ◽  
Glioblastoma Cells ◽  
Caspase 9 ◽  
Cytochrome C Release ◽  
Induced Apoptosis

Background: We have previously shown that the anti-neoplastic agent erucylphosphohomocholine (ErPC3) requires the mitochondrial 18 kDa Translocator protein (TSPO), formerly known as the peripheral-type benzodiazepine receptor (PBR), to induce cell death via the mitochondrial apoptosis pathway.Methods: With the aid of the dye JC-1 and cyclosporin A, applied to glioblastoma cells, we now investigated the significance of opening of the mitochondrial permeability transition pore (MPTP) for ErPC3-induced apoptosis in interaction with the TSPO ligands, PK 11195 and Ro5 4864. Furthermore, we measured cytochrome c release, and caspase-9 and -3 activation in this paradigm.Results: The human glioblastoma cell lines, U87MG, A172 and U118MG express the MPTP-associated TSPO, voltage-dependent anion channel and adenine nucleotide transporter. Indeed, ErPC3-induced apoptosis was inhibited by the MPTP blocker cyclosporin A and by PK 11195 and Ro5 4864 in a concentration-dependent manner. Furthermore, PK 11195 and Ro5 4864 inhibited collapse of the mitochondrial membrane potential, cytochrome c release, and caspase-9 and -3 activation caused by ErPC3 treatment.Conclusions: This study shows that PK 11195 and Ro5 4864 inhibit the pro-apoptotic function of ErPC3 by blocking its capacity to cause a collapse of the mitochondrial membrane potential. Thus, the TSPO may serve to open the MPTP in response to anti-cancer drugs such as ErPC3.

Activation of Caspases-8 and -9 Occurs In Platelets From Children with Immune, but Not Chemotherapy-Related, Thrombocytopenia.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3700-3700
Author(s):  
Jeannine Winkler ◽  
Sabine Kroiss ◽  
Margaret L. Rand ◽  
Markus Schmugge ◽  
Oliver Speer
Keyword(s):  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Caspase 3 ◽  
Ivig Therapy ◽  
Caspase 8 ◽  
Healthy Children ◽  
Caspase 9 ◽  
Platelet Counts ◽  
Ivig Administration

Abstract Abstract 3700 Apoptotic-like processes in platelets are similar to those observed during apoptosis in the cytoplasm of nucleated cells: activation of caspase-8, caspase-9, and caspase-3, loss of mitochondrial inner membrane potential, and externalization of phosphatidylserine (PS) (Leytin et al, Br J Haematol 2006; Lopez et al, J Thromb Haemost 2009). We recently showed that platelets in pediatric primary immune thrombocytopenia (ITP) have activated caspase-3 (aCASP3) and externalized PS, both of which were reduced after IVIg administration (Speer et al, Blood 2008;112: 3417). To gain a more complete understanding of the apoptosis that occurs in ITP platelets, in the present study, we investigated whether caspase-8 and caspase-9 are also activated in platelets from children with ITP, and examined whether the increase in platelet count in response to IVIg is associated with a decrease in activated caspase-8 (aCASP8) and -9 (aCASP9) in platelets, as was observed for aCASP3. In addition, we measured the mitochondrial membrane potential in platelets before and after IVIg therapy. Children with primary ITP were enrolled in this prospective study. Severity of bleeding symptoms was assessed according to a pediatric bleeding score for ITP at the time of diagnosis. Blood samples were obtained at the time of diagnosis and after IVIg therapy for measurement of platelet count and for flow cytometric analyses of platelet apoptotic-like events. In citrated platelet-rich plasma, platelets were identified as CD42 positive events; aCASP8 and aCASP9 were measured as % platelets with bound FITC-fluorescent-labeled inhibitors of activated caspases; and mitochondrial membrane potential was measured as mean fluorescence intensity of the membrane potential sensitive fluorescent tetramethylrhodamine ethyl ester (TMRE). All patients (median age 5.4 yrs, n = 8) presented with typical symptoms of acute ITP with a bleeding score of 2 – 3 and had platelet counts < 20×109/L. Results from ITP patients were compared with 2 control groups, healthy children (platelet counts: 266–348 × 109/L, median age 6.8 yrs, n = 7) and children with thrombocytopenia as a result of chemotherapy for malignancies (cTP) (platelet counts: 3–51 × 109/L, median age 10.2 yrs, n = 7). ITP patients had significantly higher proportions of platelets with aCASP8 (17.5±5.1%) and aCASP9 (16.9±5.8%) compared with both healthy children (aCASP8 1.0±0.3%; aCASP9 1.1±0.3%) and children with cTP, (aCASP8 2.2±0.4%; aCASP9 1.9±0.4%) (p<0.01-0.05). In contrast, a loss of mitochondrial membrane potential was not observed in platelets from ITP patients at baseline, in healthy controls, or cTP. All ITP patients were treated with a maximum of 3 doses of IVIg (0.4 – 0.8 g/kg/dose) and showed a rise in platelet counts to > 20 × 109/L and amelioration of bleeding symptoms by 24 – 72 hours after IVIg administration. Concomitantly, the fractions of platelets with aCASP8 and aCASP9, decreased towards control values (ITP patients after IVIg: aCASP8 7.8±5.3%; aCASP9 6.9±2.1; p=0.5 for both compared to controls). Again no change in mitochondrial potential was observed after IVIg. In summary, we have demonstrated enhancement of the platelet apoptotic-like processes of aCASP8 and aCASP9 specifically in pediatric primary ITP, which were not observed in cTP. However, the platelet mitochondrial membrane potential was unchanged in ITP (before and after IVIg) and did not differ compared cTP and healthy children. Consistent with primary ITP, the patients' platelet counts were low and increased with IVIg administration. In parallel, IVIg led to a decrease of aCASP8 and aCASP9 in the patients' platelets. Together with our previously reported results (Speer et al, Blood 2008;112: 3417), we show that apoptotic events in platelets such as activation of caspases-8, -9, and -3 and PS exposure are increased specifically in ITP but not in cTP, and are decreased after IVIg treatment. As we detected no loss of the mitochondrial membrane potential in platelets from ITP patients, it may be that apoptotic processes in these platelets are not activated by mitochondrial signaling, but rather via an extrinsic signaling cascade including caspase-8, leading to the activation of caspase-3 and caspase-9. However, the complete signaling pathway leading to caspase-8 activation in platelets of pediatric ITP remains to be elucidated. Disclosures: No relevant conflicts of interest to declare.

Itraconazole, an Oral Antifungal Drug, Inhibits Tumor Growth and Enhances Therapeutic Agent Activity in Double Hit Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5380-5380
Author(s):  
Juan J Gu ◽  
Lianjuan Yang ◽  
Benjamin Jarmusz ◽  
Daniel Cress ◽  
Cory Mavis ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Membrane Potential ◽  
Cell Viability ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Caspase 3 ◽  
Kinase Inhibitor ◽  
Proteasome Inhibitors ◽  
Double Hit Lymphoma ◽  
Double Hit

Abstract Background: Among B-cell lymphoma, double hit lymphoma (DHL) is defined by a MYC/8q24 combined with another recurrent BCL/18q21 breakpoint. DHL most affects elderly patients (median age ranged from 51 to 65 years) and have a poor prognosis with a median overall survival of 0.2-1.5 year. R+CHOP or high-intensity treatment including high-dose chemotherapy followed stem cell transplant yield to suboptimal outcomes. Therefore, there is a need to discover alternative effective agents. Itraconazole, an oral antifungal drug, was reported had potent anticancer activity in basal cell carcinoma, non-small cell lung cancer and prostate cancer by interfering with the apoptotic threshold of cancer cells. Its activity in DHL has yet to be defined. Methods: Double hit lymphoma cell lines: DOHH2, VAL and ROS50 were exposed to escalating doses of itraconazole (0-20μM) for 24, 48 and 72h. Changes in cell viability and cell cycle distribution were evaluated using the Presto Blue assay and flow cytometry respectively. IC50 was calculated by Graphpad Prism 6 software. Loss of ATP, Caspase 3/7 activation and loss of mitochondrial membrane potential (∆ψm) following itraconazole exposure were assessed by Cell Titer Glo, Caspase3 /7 detection kit and DiOC6 staining, respectively. DHL cells were exposed to itraconazole or vehicle combined with various inhibitors, such as BCL-2 inhibitor ABT199, c-MYC inhibitor JQ1, bruton's kinase inhibitor ibrutinib and different generations of proteasome inhibitors (carfilzomib or MLN4924) for 48h and cell viability was determined by Presto Blue assay. Coefficient of synergy index was calculated using the CalcuSyn software. Result: Itraconazole consistently showed potent, specific, dose-and time- dependent inhibition in DHL. In vitro exposure cells to itraconazole resulted in a loss of ATP, loss of mitochondrial membrane potential and activation of caspase 3/7 activities. Itraconazole caused G1 cell cycle arrest and decrease S phase in DHL. Moreover, itraconazole had a strong synergistic anti-tumor effect combined with various inhibitors, including BCL-2 inhibitor ABT199, c-MYC inhibitor JQ1, bruton's kinase inhibitor ibrutinib and different generations of proteasome inhibitors (bortezomib, carfilzomib, Ixazomib or MLN4924). Conclusion: Taking together, our data suggest that itraconazole had a potent anti-tumor activity against DHL. Disruption of mitochondrial membrane potential and activation of caspases may contribute its antitumor activity against DHL. It is worth noticing that combined itraconazole with DHL specific target inhibitors ABT199 or JQ1 had a strong synergistic efficacy. Our findings offered the first assessment of the efficacy of itraconazole as a novel anticancer agent in double hit lymphoma. The molecular mechanism of action of itraconazole need to be further investigated in the near further. Disclosures No relevant conflicts of interest to declare.

scholarly journals Bcl-2 Family Members and Functional Electron Transport Chain Regulate Oxygen Deprivation-Induced Cell Death

2002 ◽  
Vol 22 (1) ◽  
pp. 94-104 ◽  
Author(s):  
David S. McClintock ◽  
Matthew T. Santore ◽  
Vivian Y. Lee ◽  
Joslyn Brunelle ◽  
G. R. Scott Budinger ◽  
...  
Keyword(s):  
Cell Death ◽  
Membrane Potential ◽  
Electron Transport ◽  
Mitochondrial Membrane Potential ◽  
Electron Transport Chain ◽  
Mitochondrial Membrane ◽  
Family Members ◽  
Oxygen Deprivation ◽  
Caspase 9 ◽  
Transport Chain

ABSTRACT The mechanisms underlying cell death during oxygen deprivation are unknown. We report here a model for oxygen deprivation-induced apoptosis. The death observed during oxygen deprivation involves a decrease in the mitochondrial membrane potential, followed by the release of cytochrome c and the activation of caspase-9. Bcl-XL prevented oxygen deprivation-induced cell death by inhibiting the release of cytochrome c and caspase-9 activation. The ability of Bcl-XL to prevent cell death was dependent on allowing the import of glycolytic ATP into the mitochondria to generate an inner mitochondrial membrane potential through the F1F0-ATP synthase. In contrast, although activated Akt has been shown to inhibit apoptosis induced by a variety of apoptotic stimuli, it did not prevent cell death during oxygen deprivation. In addition to Bcl-XL, cells devoid of mitochondrial DNA (ρ° cells) that lack a functional electron transport chain were resistant to oxygen deprivation. Further, murine embryonic fibroblasts from bax −/− bak −/− mice did not die in response to oxygen deprivation. These data suggest that when subjected to oxygen deprivation, cells die as a result of an inability to maintain a mitochondrial membrane potential through the import of glycolytic ATP. Proapoptotic Bcl-2 family members and a functional electron transport chain are required to initiate cell death in response to oxygen deprivation.

scholarly journals Caspase-9-induced Mitochondrial Disruption through Cleavage of Anti-apoptotic BCL-2 Family Members

2007 ◽  
Vol 282 (46) ◽  
pp. 33888-33895 ◽  
Author(s):  
Min Chen ◽  
Alan D. Guerrero ◽  
Li Huang ◽  
Zainuer Shabier ◽  
Michael Pan ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Signaling Cascade ◽  
Caspase 9 ◽  
Endonuclease G ◽  
Chemically Induced ◽  
Chemically Induced Dimerization ◽  
Mitochondrial Disruption ◽  
Apoptosis Inducing Factor

Mitochondrial disruption during apoptosis results in the release of cytochrome c that forms apoptosomes with Apaf-1 and caspase-9. Activation of caspase-9 by dimerization in apoptosomes then triggers a caspase signaling cascade. In addition, other apoptosis signaling molecules released from the mitochondrion, such as apoptosis-inducing factor and endonuclease G, may induce caspase-9-independent apoptosis. To determine the signaling events induced by caspase-9, we used chemically induced dimerization for specific activation of caspase-9. We observed that caspase-9 dimerization resulted in the loss of mitochondrial membrane potential and the cleavage of anti-apoptotic Bcl-2, Bcl-xL, and Mcl-1. Moreover, cleavage-resistant Bcl-2, Bcl-xL, or Mcl-1 potently inhibited caspase-9-dependent loss of mitochondrial membrane potential and the release of cytochrome c. Our data suggest that a caspase-9 signaling cascade induces feedback disruption of the mitochondrion through cleavage of anti-apoptotic Bcl-2, Bcl-xL, and Mcl-1.

scholarly journals A Synthetic Pan-Aurora Kinase Inhibitor, 5-Methoxy-2-(2-methoxynaphthalen-1-yl)-4H-chromen-4-one, Triggers Reactive Oxygen Species-Mediated Apoptosis in HCT116 Colon Cancer Cells

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Jeong Yeon Lee ◽  
Sung Shin Ahn ◽  
You Jeong Jeong ◽  
Jihye Choi ◽  
Seunghyun Ahn ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Stress Responses ◽  
Mitochondrial Membrane ◽  
Kinase Inhibitor ◽  
Aurora Kinase ◽  
Genotoxic Stress ◽  
Oxygen Species ◽  
Aurora Kinase Inhibitor

Aurora kinases are Ser/Thr kinases that function as mitotic regulators. 5-Methoxy-2-(2-methoxynaphthalen-1-yl)-4H-chromen-4-one (DK1913) is a synthetic pan-Aurora kinase inhibitor. However, the mode of action of DK1913 concerning the induction of apoptosis is unclear. Here, we report that DK1913 triggered apoptosis, as revealed by flow cytometry and Annexin V staining. DK1913 enhanced the intracellular levels of reactive oxygen species (ROS) and stimulated the endoplasmic reticulum (ER) and genotoxic stress responses. We also found that DK1913 induced the loss of mitochondrial membrane potential, leading to the activation of caspase-9, caspase-7, and caspase-3. In addition, the antioxidant, butylated hydroxyanisole (BHA), abrogated DK1913-induced loss of mitochondrial membrane potential and activation of the caspase cascade. These findings demonstrate that pan-Aurora kinase inhibitor DK1913 triggers apoptosis through ROS-mediated ER and genotoxic stress responses.

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