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PubMed2026

The KEAP1-NFE2L2/NRF2 Axis in Non-Small Cell Lung Cancer Radioresistance: Redox Homeostasis and Emerging DNA Damage Response Mechanisms.

Radioresistance and local recurrence remain major barriers to effective radiotherapy in non-small cell lung cancer (NSCLC). Loss-of-function KEAP1 alterations or activating NFE2L2 alterations can stabilize NRF2, but do not alone establish sustained transcriptional activity or functional dependency. This focused narrative review evaluates clinical radiotherapy studies and mechanistically informative preclinical studies linking the KEAP1-NFE2L2/NRF2 axis to NSCLC radioresistance. We prioritized clinical studies reporting radiotherapy-specific outcomes and preclinical studies coupling NRF2-related molecular status or perturbation with radiation-response endpoints; contextual studies informed metabolic, DNA damage response (DDR), immune and normal-lung effects. Evidence most consistently supports NRF2-mediated redox protection through glutathione-dependent defense, cellular reducing capacity and antioxidant enzymes, limiting radiation-induced reactive oxygen species (ROS) accumulation and oxidative injury. Limited studies further suggest that NRF2 may affect DNA-damage signaling, checkpoint control and repair. The detailed RPA32-TOPBP1-ATR-CHK1 model is therefore considered proposed rather than established in NRF2-active NSCLC. Retrospective clinical studies associate pathogenic KEAP1/NFE2L2 alterations with impaired local control in some radiotherapy-treated cohorts, but do not justify treating genomic status, protein abundance, transcriptional activity and functional dependency as equivalent measures or demonstrate treatment-predictive value. NRF2-mediated normal-lung protection also constrains systemic inhibition. Prospective studies integrating molecular classification, radiation-response endpoints, local control and normal-tissue toxicity are required before biomarker-guided radiosensitization can be considered.

DNA damage response↗

PubMed2006

Selective induction of necrotic cell death in cancer cells by beta-lapachone through activation of DNA damage response pathway.

Most efforts thus far have been devoted to develop apoptosis inducers for cancer treatment. However, apoptotic pathway deficiencies are a hallmark of cancer cells. We propose that one way to bypass defective apoptotic pathways in cancer cells is to induce necrotic cell death. Here we show that selective induction of necrotic cell death can be achieved by activation of the DNA damage response pathways. While beta-lapachone induces apoptosis through E2F1 checkpoint pathways, necrotic cell death can be selectively induced by beta-lapachone in a variety of cancer cells. We found that beta-lapachone, unlike DNA damaging chemotherapeutic agents, transiently activates PARP1, a main regulator of the DNA damage response pathway, both in vitro and in vivo. This occurs within minutes of exposure to beta-lapachone, resulting in selective necrotic cell death. Inhibition of PAR blocked beta-lapachone-induced necrosis. Furthermore, necrotic cell death induced by beta-lapachone was significantly reduced in PARP1 knockout cell lines. Our data suggest that selective necrotic cell death can be induced through activation of DNA damage response pathways, supporting the idea of selective necrotic cell death as a therapeutic strategy to eliminate cancer cells.

Animals↗

PubMed2005

Role of RNA polymerase II carboxy terminal domain phosphorylation in DNA damage response.

The phosphorylation of C-terminal domain (CTD) of Rpb1p, the largest subunit of RNA polymerase II plays an important role in transcription and the coupling of various cellular events to transcription. In this study, its role in DNA damage response is closely examined in Saccharomyces cerevisiae, focusing specifically on several transcription factors that mediate or respond to the phosphorylation of the CTD. CTDK-1, the pol II CTD kinase, FCP1, the CTD phosphatase, ESS1, the CTD phosphorylation dependent cis-trans isomerase, and RSP5, the phosphorylation dependent pol II ubiquitinating enzyme, were chosen for the study. We determined that the CTD phosphorylation of CTD, which occurred predominantly at serine 2 within a heptapeptide repeat, was enhanced in response to a variety of sources of DNA damage. This modification was shown to be mediated by CTDK-1. Although mutations in ESS1 or FCP1 caused cells to become quite sensitive to DNA damage, the characteristic pattern of CTD phosphorylation remained unaltered, thereby implying that ESS1 and FCP1 play roles downstream of CTD phosphorylation in response to DNA damage. Our data suggest that the location or extent of CTD phosphorylation might be altered in response to DNA damage, and that the modified CTD, ESS1, and FCP1 all contribute to cellular survival in such conditions.

DNA Damage↗

PubMed2006

Tip60 in DNA damage response and growth control: many tricks in one HAT.

The Tip60 histone acetyltransferase is part of an evolutionarily conserved multisubunit complex, NuA4, which is recruited by many transcription factors to their target promoters, where it is thought to participate in histone acetylation and transcriptional activation. These transcription factors include tumor promoters and also tumor suppressors, such as p53, which links Tip60 to DNA damage responses. Tip60 also has transcription-independent roles in DNA damage responses. First, independently from NuA4, Tip60 binds the kinases ataxia-telangiectasia mutated (ATM) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and participates in their activation by DNA double-strand breaks. Second, NuA4 is recruited to the chromatin surrounding the breaks and, through a series of chromatin modifications, contributes to the dynamics of DNA repair. These molecular activities might endow Tip60 with multiple and potentially antagonistic biological functions.

Acetyltransferases↗

PubMed1998

Human papillomavirus type 16 E6 and E7 oncogenes abrogate radiation-induced DNA damage responses in vivo through p53-dependent and p53-independent pathways.

E6 and E7 oncoproteins from high risk human papillomaviruses (HPVs) transform cells in tissue culture and induce tumors in vivo. Both E6, which inhibits p53 functions, and E7, which inhibits pRb, can also abrogate growth arrest induced by DNA-damaging agents in cultured cells. In this study, we have used transgenic mice that express HPV-16 E6 or E7 in the epidermis to determine how these two proteins modulate DNA damage responses in vivo. Our results demonstrate that both E6 and E7 abrogate the inhibition of DNA synthesis in the epidermis after treatment with ionizing radiation. Increases in the levels of p53 and p21 proteins after irradiation were suppressed by E6 but not by E7. Through the study of p53-null mice, we found that radiation-induced growth arrest in the epidermis is mediated through both p53-dependent and p53-independent pathways. The abrogation of radiation responses in both E6 and E7 transgenic mice was more complete than was seen in the p53-null epidermis. We conclude that E6 and E7 each have the capacity to modulate p53-dependent as well as p53-independent cellular responses to radiation. Additionally, we found that the conserved region (CR) 1 and CR2 domains in E7 protein, which are involved in the inactivation of pRb function and required for E7's transforming function, were also required for E7 to modulate DNA damage responses in vivo. Thus pRb and/or pRb-like proteins likely mediate both p53-dependent and p53-independent responses to radiation.

Animals↗

PubMed2006

Replication-dependent DNA damage response triggered by roscovitine induces an uncoupling of DNA replication proteins.

The cyclin-dependent kinase (CDK) inhibitor roscovitine is under evaluation in clinical trials for its antiproliferative properties. Roscovitine arrests cell cycle progression in G(1) and in G(2) phase by inhibiting CDK2 and CDK1, and possibly CDK7 and CDK9. However, the effects of CDK2 inhibition in S-phase cells have been not fully investigated. Here, we show that a short-term treatment with roscovitine is sufficient to inhibit DNA synthesis, and to activate a DNA damage checkpoint response, as indicated by phosphorylation of p53-Ser15, replication protein A, and histone H2AX. Analysis of DNA replication proteins loaded onto DNA during S phase showed that the amount of proliferating cell nuclear antigen (PCNA), a cofactor of DNA replication enzymes, was significantly reduced by roscovitine. In contrast, chromatin-bound levels of DNA polymerase delta, DNA ligase I and CDK2, were stabilized. Checkpoint inhibition with caffeine could rescue PCNA disassembly only partially, pointing to additional effects due to CDK2 inhibition and the presence of replication stress. These results suggest that in S-phase cells, roscovitine induces checkpoint-dependent and -independent effects, leading to stabilization of replication forks and an uncoupling between PCNA and PCNA-interacting proteins.

Cell Proliferation↗

PubMed1999

The role of Schizosaccharomyces pombe Rad32, the Mre11 homologue, and other DNA damage response proteins in non-homologous end joining and telomere length maintenance.

The Schizosaccharomyces pombe homologue of Mre11, Rad32, is required for repair of UV- and ionising radiation-induced DNA damage and meiotic recombination. In this study we have investigated the role of Rad32 and other DNA damage response proteins in non-homologous end joining (NHEJ) and telomere length maintenance in S.pombe. We show that NHEJ in S.pombe occurs by an error-prone mechanism, in contrast to the accurate repair observed in Saccharomyces cerevisiae. Deletion of the rad32 gene results in a modest reduction in NHEJ activity and the remaining repair events that occur are accurate. Mutations in two of the phosphoesterase motifs in Rad32 have no effect on the efficiency or accuracy of end joining, suggesting that the role of Rad32 protein may be to recruit another nuclease(s) for processing during the end joining reaction. We also analysed NHEJ in other DNA damage response mutants and showed that the checkpoint mutant rad3-d and two recombination mutants defective in rhp51 and rhp54 (homologues of S.cerevisiae RAD51 and RAD54, respectively) are not affected. However disruption of rad22, rqh1 and rhp9 / crb2 (homologues of the S.cerevisiae RAD52, SGS1 and RAD9 genes) resulted in increased NHEJ activity. Telomere lengths in the rad32, rhp9 and rqh1 null alleles were reduced to varying extents intermediate between the lengths observed in wild-type and rad3 null cells.

DNA Damage↗

PubMed2005

New opportunities in chemosensitization and radiosensitization: modulating the DNA-damage response.

Many current cancer treatments, including certain classes of chemotherapeutics and radiation, induce cytotoxicity by damaging DNA. However, many cancers are resistant to these therapies, which represents a significant challenge in the clinic. Thus, modulating DNA-damage responses to selectively enhance the sensitivity of cancer cells to these therapies is highly desirable. When DNA damage is detected, DNA checkpoint mechanisms are activated to halt cells at various phases of the cell cycle. Simultaneously, DNA-damage sensors transduce signals to activate DNA-repair mechanisms via de novo expression or post-translational modification of enzymes required for DNA repair. p53 is the major player in a checkpoint that arrests cells at the G1/S boundary, while checkpoint kinase (Chk)1 is critical for the G2/M checkpoint and also the S checkpoint that prevents cell cycle progression after replication defects (intra-S-phase checkpoint) or S/M uncoupling (S/M checkpoint). Poly(ADP-ribose) polymerase is involved in sensing DNA single-strand breaks and inducing DNA repair via poly(ADP-ribosyl)ating various DNA-binding and DNA-repair proteins. In this review, strategies for implementing small-molecule inhibitors of poly(ADP-ribose) polymerase and Chk1, which are emerging as potential adjuncts to current therapies, are discussed.

Antineoplastic Agents↗

PubMedDate not supplied

DNA damage responses in cell cycle G2 phase and mitosis--tracking and targeting.

BACKGROUND: In order to determine temporal responses of cell cycle populations to DNA damage, a rational combination of cell cycle analyses is critical. Moreover, the targeting of cell cycle checkpoint responses may modify the cytotoxic effect of DNA damage. MATERIALS AND METHODS: The characteristics of cell cycle populations (DNA content, cell cycle transitioning of S phase cells and size of mitotic cell fraction within the total G2/M phase population) in HeLa cells exposed to ionizing radiation were analyzed using three individual flow cytometry-based assays. The potential radiosensitization from inhibiting DNA damage responses was assessed by the colony formation assay. RESULTS: Irradiation resulted in an initial accumulation of S phase cells in G2 phase, from which the arrested cells were subsequently released to enter mitosis. Upon drug inhibition of G2 checkpoint signaling or mitotic progression, the cytotoxic effect of ionizing radiation on the HeLa cells was amplified. CONCLUSION: DNA damage-induced cell cycle responses, analyzed by selected cytometry assays and modified by specific targeting, might contribute to an understanding of how to improve radiotherapy outcome.

Cell Division↗

PubMed2021

DNA Damage Responses during the Cell Cycle: Insights from Model Organisms and Beyond.

Genome damage is a threat to all organisms. To respond to such damage, DNA damage responses (DDRs) lead to cell cycle arrest, DNA repair, and cell death. Many DDR components are highly conserved, whereas others have adapted to specific organismal needs. Immense progress in this field has been driven by model genetic organism research. This review has two main purposes. First, we provide a survey of model organism-based efforts to study DDRs. Second, we highlight how model organism study has contributed to understanding how specific DDRs are influenced by cell cycle stage. We also look forward, with a discussion of how future study can be expanded beyond typical model genetic organisms to further illuminate how the genome is protected.

Animals↗

PubMed2005

Dysfunction of lamin A triggers a DNA damage response and cellular senescence.

In higher eukaryotes, the nuclear lamins play an important role in maintaining the integrity of the nuclear envelope and the nucleus itself. Two recent papers show that a mutation that affects the processing of one of the nuclear lamins, lamin A, results in increased sensitivity to DNA damaging agents, an elevated DNA damage response, and a senescent phenotype. These studies underscore the role of the nuclear envelope in maintaining genomic stability and the interplay between nuclear architecture and the DNA damage response.

Cell Line↗

PubMed2006

Oncogenes and the DNA damage response: Myc and E2F1 engage the ATM signaling pathway to activate p53 and induce apoptosis.

Activation of the ATM DNA damage response pathway is commonly observed in a variety of early-stage neoplasias. It has been proposed that this checkpoint response functions to suppress the development of cancer. A recent report from our laboratory demonstrates that ATM does indeed function to suppress tumorigenesis by responding to at least some oncogenic stresses. Transgenic expression of Myc is found to cause DNA damage in vivo and ATM is shown to respond to this damage by inducing the accumulation and phosphorylation of p53. In the absence of ATM, p53-dependent apoptosis is reduced and epithelial tumorigenesis is accelerated in Myc transgenic mice. Deregulated expression of the E2F1 transcription factor also elicits an ATM-dependent checkpoint response that activates p53 and promotes apoptosis, although the mechanism by which E2F1 and Myc stimulate ATM may differ. These findings have relevance for understanding why the ATM pathway is activated in many human cancers, what generates the selective pressure for p53 inactivation during tumorigenesis, and why AT patients and carriers are predisposed to developing cancer.

Animals↗

PubMed2001

p53 protein at the hub of cellular DNA damage response pathways through sequence-specific and non-sequence-specific DNA binding.

Our environment contains physical, chemical and pathological agents that challenge the integrity of our DNA. In addition to DNA repair, higher multicellular organisms have evolved multiple pathways of response to damage including programmed cell death-apoptosis. The p53 protein appears to sense multiple types of DNA damage and coordinate with multiple options for cellular response. The p53 protein activities depend upon its DNA binding. Specific p53 protein post-translational modifications are required for efficient sequence-specific binding and transcriptional activities. Non-sequence-specific DNA binding may involve a wide spectrum of p53 proteins and predominate as DNA damage is more severe or p53 protein is more highly induced. p53 protein is not strictly required for DNA damage sensing and repair. Rather, p53 protein may govern an apoptosis checkpoint through competition with DNA repair proteins for non-sequence-specific binding to exposed single-stranded regions in the DNA duplex. This model provides a framework for testing mechanisms of p53-mediated apoptosis dependent upon the p53 protein modification state, the level of p53 protein accumulation, the level of DNA damage and the capacity of the damaged cell to repair.

Animals↗

PubMed2006

BRIT1 regulates early DNA damage response, chromosomal integrity, and cancer.

BRIT1, initially identified as an hTERT repressor, has additional functions at DNA damage checkpoints. Here, we demonstrate that BRIT1 formed nuclear foci minutes after irradiation. The foci of BRIT1 colocalized with 53BP1, MDC1, NBS1, ATM, RPA, and ATR. BRIT1 was required for activation of these elements, indicating that BRIT1 is a proximal factor in the DNA damage response pathway. Depletion of BRIT1 increased the accumulation of chromosomal aberrations. In addition, decreased levels of BRIT1 were detected in several types of human cancer, with BRIT1 expression being inversely correlated with genomic instability and metastasis. These results identify BRIT1 as a crucial DNA damage regulator in the ATM/ATR pathways and suggest that it functions as a tumor suppressor gene.

Base Sequence↗

PubMed2006

Ras induces chromosome instability and abrogation of the DNA damage response.

Ras mutations are frequent in thyroid tumors, the most common endocrine malignancy. The ability of Ras to transform thyroid cells is thought to rely on its mitogenic activity. Unexpectedly, acute expression of activated Ras in normal rat thyroid cells induced a DNA damage response, followed by apoptosis. Notably, a subpopulation of cells evaded apoptosis and emerged with features of transformation, including the loss of epithelial morphology, dedifferentiation, and the acquisition of hormone- and anchorage-independent proliferation. Strikingly, the surviving cells showed marked chromosomal instability. Acutely, Ras stimulated replication stress as evidenced by the induction of ataxia telangiectasia mutated and Rad3-related protein kinase (ATR) activity (Chk1 phosphorylation) and of gammaH2A.X, a marker of DNA damage. Despite the activation of a checkpoint, cells continued through mitosis in the face of DNA damage, resulting in an increase in cells harboring micronuclei, an indication of defects in chromosome segregation and other forms of chromosome damage. Cells that survived exposure to Ras continued to exhibit replication stress (ATR activation) but no longer exhibited gammaH2A.X or full activation of p53. When rechallenged with Ras or DNA-damaging agents, the surviving cells were more resistant to apoptosis than parental cells. These data show that acute expression of activated Ras is sufficient to induce chromosomal instability in the absence of other signals, and suggest that Ras-induced chromosomal instability arises as a consequence of defects in the processing of DNA damage. Hence, abrogation of the DNA damage response may constitute a novel mechanism for Ras transformation.

Animals↗

PubMed2000

BRCA1 effects on the cell cycle and the DNA damage response are linked to altered gene expression.

The breast and ovarian cancer susceptibility gene product BRCA1 has been reported to be expressed in a cell cycle-dependent manner; possess transcriptional activity; associate with several proteins, including the p53 tumor suppressor; and play an integral role in certain types of DNA repair. We show here that ectopic expression of BRCA1 using an adenovirus vector (Ad-BRCA1) leads to dephosphorylation of the retinoblastoma protein accompanied by a decrease in cyclin-dependent kinase activity. Flow cytometric analysis on Ad-BRCA1-infected cells revealed a G(1) or G(2) phase accumulation. High density cDNA array screening of colon, lung, and breast cancer cells identified several genes affected by BRCA1 expression in a p53-independent manner, including DNA damage response genes and genes involved in cell cycle control. Notable changes included induction of the GADD45 and GADD153 genes and a reduction in cyclin B1 expression. Therefore, BRCA1 has the potential to modulate the expression of genes and function of proteins involved in cell cycle control and DNA damage response pathways.

Adenoviridae↗

PubMed2005

DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis.

During the evolution of cancer, the incipient tumour experiences 'oncogenic stress', which evokes a counter-response to eliminate such hazardous cells. However, the nature of this stress remains elusive, as does the inducible anti-cancer barrier that elicits growth arrest or cell death. Here we show that in clinical specimens from different stages of human tumours of the urinary bladder, breast, lung and colon, the early precursor lesions (but not normal tissues) commonly express markers of an activated DNA damage response. These include phosphorylated kinases ATM and Chk2, and phosphorylated histone H2AX and p53. Similar checkpoint responses were induced in cultured cells upon expression of different oncogenes that deregulate DNA replication. Together with genetic analyses, including a genome-wide assessment of allelic imbalances, our data indicate that early in tumorigenesis (before genomic instability and malignant conversion), human cells activate an ATR/ATM-regulated DNA damage response network that delays or prevents cancer. Mutations compromising this checkpoint, including defects in the ATM-Chk2-p53 pathway, might allow cell proliferation, survival, increased genomic instability and tumour progression.

Allelic Imbalance↗

PubMed2006

A systems approach to mapping DNA damage response pathways.

Failure of cells to respond to DNA damage is a primary event associated with mutagenesis and environmental toxicity. To map the transcriptional network controlling the damage response, we measured genomewide binding locations for 30 damage-related transcription factors (TFs) after exposure of yeast to methyl-methanesulfonate (MMS). The resulting 5272 TF-target interactions revealed extensive changes in the pattern of promoter binding and identified damage-specific binding motifs. As systematic functional validation, we identified interactions for which the target changed expression in wild-type cells in response to MMS but was nonresponsive in cells lacking the TF. Validated interactions were assembled into causal pathway models that provide global hypotheses of how signaling, transcription, and phenotype are integrated after damage.

DNA Damage↗