Cellular Responses to DNA Damage

Norbury, Chris J.; Hickson, Ian D.

doi:10.1146/annurev.pharmtox.41.1.367

Cited by 518 publications

(326 citation statements)

References 210 publications

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“…DNA damage includes abnormalities such as single and double strand breaks, 8-hydroxydeoxyguanosine residues and DNA adducts. 23,24 The present results revealed that SK228 could cause DNA damage by binding to the minor groove of DNA, intercalating into DNA and increasing ROS production. However, the binding effects are not strong at lower concentrations.…”

Section: Discussionmentioning

confidence: 56%

The novel indole compound SK228 induces apoptosis and FAK/Paxillin disruption in tumor cell lines and inhibits growth of tumor graft in the nude mouse

Huang

Hsu

Chen

et al. 2011

Intl Journal of Cancer

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Drugs in clinical use with indole structure exhibit side effects. Therefore, to search for indole compounds with more efficacy and less side effect for cancer therapy, we developed a novel indole compound SK228 and examined its effects and mechanisms on antitumor growth and invasion inhibition in cell and tumor xenografts in nude mice models. SK228 significantly inhibited growth of different lung and esophageal cancer cell lines at sub-micromolar range, but not normal lung cells. SK228 induced DNA damages mainly by producing reactive oxygen species (ROS) resulting in apoptosis. SK228 treatment increased the release of cytochrome c into the cytosol along with the increased activity of caspase-3 and -9 without affecting caspase-8, whereas these effects were attenuated by ROS inhibitor. The expression levels of BCL-2 family regulators were also affected. Moreover, low-dose SK228 significantly reduced the invasion of cancer cells. The active phosphorylated form of FAK/Paxillin signaling pathway proteins and active form of RhoA were decreased. Moreover, the F-actin cytoskeleton was disrupted after low-dose SK228 treatment. Growth of an A549 tumor cell xenograft was markedly inhibited without significant side effects. SK228-induced apoptosis was confirmed by terminal deoxynucleotidyl transferase dUTP nick end labeling assay and immunohistochemistry of cleaved caspase-3 in tumors from treated mice. Our study provides the first evidence that SK228 exhibits cancer cell-specific cytotoxicity by inducing mitochondria-mediated apoptosis. In addition, SK228 inhibits cancer cell invasion via FAK/Paxillin disruption at noncytotoxic doses. SK228 can be further tested as a pharmaceutical compound for cancer treatment.There are three standard therapies for cancer treatment including surgery, radiotherapy and chemotherapy. Chemotherapy has a role either as strategic treatment for locally advanced disease or as a palliative treatment for metastatic tumors. 1,2 However, clinical use of chemotherapy is still unsatisfactory due to limited response rate, small survival benefit and poor prognosis. Therefore, the development of novel anticancer drug, which is more effective and shows less side effect for cancer patients, is urgently needed.Several studies have indicated that compounds containing indole structure are highly cytotoxic against many tumoral cell lines, and the indole ring seems to be the core nucleus of several potent tubulin polymerization inhibitors. 3 The most wildly used clinical antimicrotubule drugs containing indole structure is Vinca alkaloids. They are also known as microtubule-destabilizing agents, which includes natural compound vinblastine, vincristine and two semisynthetic derivatives, vindesine and vinorelbine. 4 Several new compounds containing indole structure isolated from natural sources or synthesized were shown to have high potential for cancer treatment. For example, indole-3-carbinol (I3C) was isolated from cruciferous vegetables with high potential for cancer therapy. I3C and its metabolites inhibited ...

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Section: Discussionmentioning

confidence: 56%

The novel indole compound SK228 induces apoptosis and FAK/Paxillin disruption in tumor cell lines and inhibits growth of tumor graft in the nude mouse

Huang

Hsu

Chen

et al. 2011

Intl Journal of Cancer

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“…These DSBs are induced by endogenous and exogenous factors, including exposure to ionizing radiation (IR) and radiomimetic drugs, collapse of replication forks and programmed cleavage by specific endonucleases during meiotic recombination and V(D)J recombination. [12][13][14][15] DSBs are potent triggers of cell cycle arrest and apoptosis. 14,16 The effective and accurate regulation of DNA DSB repairs is essential for genomic integrity.…”

mentioning

confidence: 99%

“…[12][13][14][15] DSBs are potent triggers of cell cycle arrest and apoptosis. 14,16 The effective and accurate regulation of DNA DSB repairs is essential for genomic integrity. Double strand breaks are especially dangerous during S phase when single stranded DNA molecules are processed.…”

mentioning

confidence: 99%

DNA damage response involves modulation of Ku70 and Rb functions by cyclin A1 in leukemia cells

Bäumer

Yin

et al. 2007

Intl Journal of Cancer

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Cyclin A1 plays a critical role in hematopoietic malignancies, notably, acute myeloid leukemia. The molecular mechanisms of cyclin A1 action are incompletely understood. Here, we show that cyclin A1 functions are mediated by the retinoblastoma and the Ku70 pathway. High levels of cyclin A1 and the associated CDK2 kinase activity were associated with increasing levels of phosphorylated retinoblastoma in vivo. UV irradiation induced a switch of the CDK2 towards cyclin A1, with accordance to changes in CDK2 kinase activity. The C-terminus of cyclin A1 directly interacted with Ku70, and DNA binding activity of Ku70 was modulated by cyclin A1/ CDK2 and phosphatase treatment. Cyclin A1-deficiency induced by shRNA increased apoptosis that is induced by DNA damage and death receptor ligands. Taken together, these analyses demonstrate that cyclin A1 exerts antiapoptotic functions by interacting with retinoblastoma and Ku proteins in leukemia cells. ' 2007 Wiley-Liss, Inc.Key words: cyclin A1; cell cycle control; DNA repair; apoptosis Cell cycle dysregulation is one of the key phenomena in the pathogenesis of cancer. Cyclins and cyclin-dependent kinases (CDKs) are essential components for cell cycle control and development in eukaryotes. An important concept is that cyclin D-CDK4/CDK6 phosphorylate Rb. Hyperphosphorylation by cyclin E/CDK2 or cyclin E/CDK1 at additional sites releases E2F from E2F/RB complexes and allows transcriptional activation of cell cycle progression genes. 1-4 CDK2/cyclin A2 complexes actively regulate DNA replication. 5,6 Aberration of cyclin/CDK activity is commonly associated with tumor formation. [7][8][9][10] Genomic instability is another key feature of tumorigenesis. Mammalian cells have developed a number of repair systems to combat DNA damage and to maintain genomic integrity. 11 Double-strand breaks (DSBs) are the most severe types of DNA lesions. These DSBs are induced by endogenous and exogenous factors, including exposure to ionizing radiation (IR) and radiomimetic drugs, collapse of replication forks and programmed cleavage by specific endonucleases during meiotic recombination and V(D)J recombination. [12][13][14][15] DSBs are potent triggers of cell cycle arrest and apoptosis. 14,16 The effective and accurate regulation of DNA DSB repairs is essential for genomic integrity. Double strand breaks are especially dangerous during S phase when single stranded DNA molecules are processed.Recently, we discovered an important link between cell cycle regulation and DNA DSB repair. 17 DSBs repair can be modulated by A-type cyclins and especially cyclin A1, an alternative A-type cyclin. It is highly expressed in the testis and it plays an important role in spermatogenesis. 18,19 Male mice with cyclin A1 deletion are sterile due to cell cycle arrest and enhanced apoptosis. 20 More recent data suggest that cyclin A1 acts as a dose-dependent regulator of the successful production of haploid cells. 21 In addition to testicular expression, high levels of cyclin A1 have been found in several leukem...

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“…A sperm becomes positively charged when it completely loses the negatively charged glycoproteins anchored/adhered on its membrane. It is well known that apoptosis is a mechanism to eliminate dysfunctional cells [52]. During apoptosis in sperm, the integrity of the membrane is lost due to the translocation of phosphatidylserine [53], during which the phosphatidylserine is shifted from the interior to the exterior of the plasma membrane [54,55].…”

Section: Discussionmentioning

confidence: 99%

Optimization of microelectrophoresis to select highly negatively charged sperm

Lee¹,

Murphy²,

Aston³

et al. 2016

J Assist Reprod Genet

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Purpose The sperm membrane undergoes extensive surface remodeling as it matures in the epididymis. During this process, the sperm is encapsulated in an extensive glycocalyx layer, which provides the membrane with its characteristic negative electrostatic charge. In this study, we develop a method of microelectrophoresis and standardize the protocol to isolate sperm with high negative membrane charge. Methods Under an electric field, the percentage of positively charged sperm (PCS), negatively charged sperm (NCS), and neutrally charged sperm was determined for each ejaculate prior to and following density gradient centrifugation (DGC), and evaluated for sperm DNA damage, and histone retention. Subsequently, PCS, NCS, and neutrally charged sperm were selected using an ICSI needle and directly analyzed for DNA damage. Results When raw semen was analyzed using microelectrophoresis, 94 % were NCS. In contrast, DGC completely or partially stripped the negative membrane charge from sperm resulting PCS and neutrally charged sperm, while the charged sperm populations are increased with an increase in electrophoretic current. Following DGC, high sperm DNA damage and abnormal histone retention were inversely correlated with percentage NCS and directly correlated with percentage PCS. NCS exhibited significantly lower DNA damage when compared with control (P < 0.05) and PCS (P < 0.05). When the charged sperm population was corrected for neutrally charged sperm, sperm DNA damage was strongly associated with NCS at a lower electrophoretic current. Conclusion The results suggest that selection of NCS at lower current may be an important biomarker to select healthy sperm for assisted reproductive treatment.

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Cellular Responses to DNA Damage

Cited by 518 publications

References 210 publications

The novel indole compound SK228 induces apoptosis and FAK/Paxillin disruption in tumor cell lines and inhibits growth of tumor graft in the nude mouse

The novel indole compound SK228 induces apoptosis and FAK/Paxillin disruption in tumor cell lines and inhibits growth of tumor graft in the nude mouse

DNA damage response involves modulation of Ku70 and Rb functions by cyclin A1 in leukemia cells

Optimization of microelectrophoresis to select highly negatively charged sperm

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