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PubMed2003

Potentiation of DNA-damage-induced cytotoxicity by G2 checkpoint abrogators.

Cell cycle checkpoints are activated in response to DNA-damage to ensure that accurate copies of the cellular genome are passed on to the next generation and to avoid replication and segregation of damaged DNA. These cellular control systems can be overcome by combining conventional DNA-damaging agents with compounds that target the cell cycle regulatory pathways, to enhance cytotoxicity. Tumor cells often comprise a corrupted G(1) cell cycle checkpoint while the G(2) cell cycle checkpoint is still intact. This review describes the concept of G(2) checkpoint abrogation with recognized (methylxanthines, UCN-01) and novel G(2) checkpoint abrogators to potentiate the cytotoxicity of DNA-damaging drugs and ionizing radiation. It illustrates the potential of G(2) checkpoint abrogators to preferentially sensitize p53-mutated, treatment resistant tumor cells for genotoxic treatment. Identification of the targets of caffeine and UCN-01 to be key-players of the G(2) checkpoint (ATM/ATR and Chk1, respectively) promoted the search for novel inhibitors of this checkpoint. Even though a direct causal link between G(2) checkpoint abrogation and chemo-/radiosensitization is difficult to prove the multitude of these novel compounds validate that inhibition of critical elements of the G(2) checkpoint (ATM/ATR-Chk1/Chk2-CDC25C-cascade) potentiates the cytotoxicity of DNA-damaging agents.

Alkaloids↗
PubMed2001

Cell cycle regulation of c-Jun N-terminal kinase activity at the centrosomes.

The c-Jun N-terminal kinase (JNK), a subgroup of the mitogen-activated protein kinase (MAPK) family of serine/threonine kinases, has established functions in cell growth and apoptosis. While the mechanisms are unclear, JNK has also been also implicated in signaling pathways that initiate cell cycle checkpoints and cell cycle progression. By following the localization of active and inactive JNK during the cell cycle, we have found that the majority of cellular JNK is soluble and present in the cytoplasm and the nucleus. Interestingly, insoluble fractions of JNK are also localized in nuclear and cytoplasmic speckles, and to the centrosomes. While JNK is associated with the centrosome throughout the cell cycle, it is only active at the centrosome from S phase through anaphase. This novel localization of centrosomal JNK is a possible link between JNK-activating stimuli and centrosome or cell cycle events.

Animals↗
PubMed2001

Hepatitis B virus X protein: a multifunctional viral regulator.

Hepatitis B Virus (HBV) infection is one of the major causes of hepatocellular carcinoma (HCC). X protein (HBx) has been suspected to be oncogenic, although the precise role(s) remain uncertain. HBx is a multifunctional viral regulator that modulates transcription, cell responses to genotoxic stress, protein degradation, and signaling pathways. These modulations affect viral replication and viral proliferation, directly or indirectly. HBx also affects cell cycle checkpoints, cell death, and carcinogenesis. This article presents an overview of the progress in HBx research over the past several years.

Apoptosis↗
PubMed1999

C-myc overexpression and p53 loss cooperate to promote genomic instability.

p53 monitors genomic integrity at the G1 and G2/M cell cycle checkpoints. Cells lacking p53 may show gene amplification as well as the polyploidy or aneuploidy typical of many tumors. The pathways through which this develops, however, are not well defined. We demonstrate here that the combination of p53 inactivation and c-myc overexpression in diploid cells markedly accelerates the spontaneous development of tetraploidy. This is not seen with either N-myc or L-myc. Tetraploidy is accompanied by significantly higher levels of cyclin B and its associated cdc2 kinase activity. Mitotic spindle poisons accelerate the appearance of tetraploidy in cells either lacking functional p53 or overexpressing c-myc whereas the combination is additive. Restoration of p53 function in cells overexpressing c-myc causing rapid apoptosis, indicating that cells yet to become tetraploid have nonetheless suffered irreversible genomic and/or mitotic spindle damage. In the face of normal p53 function, such damage would either be repaired or trigger apoptotis. We propose that loss of p53 and overexpression of c-myc permits the emergence and survival of cells with increasingly severe damage and the eventual development of tetraploidy.

Animals↗
PubMed2002

Ubiquitination capabilities in response to neocarzinostatin and H(2)O(2) stress in cell lines from patients with ataxia-telangiectasia.

The human genetic disorder ataxia-telangiectasia (A-T) is due to lack of functional ATM, a protein kinase which is involved in cellular responses to DNA double strand breaks (DSBs) and possibly other oxidative stresses, as well as in regulation of several fundamental cellular functions. Studies regarding responses in A-T cells to the induction of DSBs utilize ionizing radiation or radiomimetic chemicals, such as neocarzinostatin (NCS), which induce DNA DSBs. This critical DNA lesion activates many defense systems, such as the cell cycle checkpoints. The cell cycle is also regulated through a timed and coordinated degradation of regulatory proteins via the ubiquitin pathway. Our recent studies indicate that the ubiquitin pathway is influenced by the cellular redox status and that it is the major cellular pathway for removal of oxidized proteins. Accordingly, we hypothesized that the absence of a functional ATM protein might involve perturbations to the ubiquitin pathway as well. We show here that upon treatment with NCS, there was a transient 50-70% increase in endogenous ubiquitin conjugates in A-T and wt lymphoblastoid cells. Ubiquitin conjugation capabilities per se and levels of substrates for conjugation were also similarly enhanced in wt and A-T cells upon NCS treatment. We also compared the ubiquitination response in A-T and wt cells using H(2)O(2) as the stress, in view of preexisting evidence of the effects of H(2)O(2) on ubiquitination capabilities in other types of cells. As with NCS treatment, there was an approximately 45% increase in endogenous ubiquitin conjugates by 2-4 h after exposure to H(2)O(2). Both cell types showed a rapid 50-150% increase in de novo formed 125I-ubiquitin conjugates. As compared with wt cells, unexposed A-T cells had higher endogenous levels of conjugates and enhanced conjugation capability. However, A-T cells mounted a more muted ubiquitination response to the stress. The enhanced ubiquitin conjugation in unstressed A-T cells and attenuated ability of these cells to respond to stress are consistent with the A-T cells being under oxidative stress and with their having an 'aged' phenotype. The indication that ubiquitin conjugate levels and ubiquitin conjugation capabilities are enhanced upon oxidative stress without significant changes in GSSG/GSH ratios indicates that assays of ubiquitination provide a sensitive measure of cellular stress. The data also add support to the impression that potentiated ubiquitination response to mild oxidative stress is a generalizable phenomenon.

Antibiotics, Antineoplastic↗
PubMed2001

Identification of the human homologue of the early-growth response gene Snk, encoding a serum-inducible kinase.

Murine serum inducible kinase (mSnk) was recently cloned and characterized as an early-growth response gene involved in cell proliferation. Here we report the isolation and characterization of its human homologue, named hSnk. Sequence comparison shows that hSnk is highly conserved and its deduced protein sequence shares a significant amino acid identity with mSnk and rSnk proteins, as well as with other polo family kinase gene products. A survey of hSnk expression reveals that while a wide variety of human tissues express a low to moderate level of hSnk transcripts, fetal tissues, testis, and spleen express the most abundant hSnk transcripts. In addition, serum stimulation rapidly induces hSnk expression in fibroblast cells, reaching the peak level of induction within one hour post treatment. Considering that Plk and Prk, two other known human polo-family kinases, control cell cycle checkpoint and cell cycle progression, our current observations suggest that hSnk may also play an important role in cells undergoing rapid cell division or having a high mitotic index.

Adenosine Triphosphate↗
PubMed1997

Genetic instability in animal tumorigenesis models.

In this review I have attempted to a describe some of the recent mouse tumour models and their impact on our understanding of cancer aetiology. The focus has been on cell cycle regulatory genes and DNA repair genes which are likely to affect cancer development at least in part through genetic instability mechanisms. The cell cycle regulatory genes classified as tumour suppressors, TP53 and RB, maintain genomic stability and inhibit cancer through their roles in preserving cell cycle checkpoints. The cell cycle inhibitors have variable effects on cancer prevention, and their role in preserving genetic stability remains largely unexplored. The DNA repair gene models described here show the most direct connection between genetic instability and cancer, even in the absence of demonstrable cell cycle effects. It should be clear that the development of mice deficient in cell cycle control or DNA repair will provide useful tools for studying the interplay of these processes with genetic instability and cancer. Important new insights into the mechanisms of cancer initiation and progression are likely to come increasingly from such models in the coming years.

Animals↗
PubMed1999

Cell cycle control, checkpoint mechanisms, and genotoxic stress.

The ability of cells to maintain genomic integrity is vital for cell survival and proliferation. Lack of fidelity in DNA replication and maintenance can result in deleterious mutations leading to cell death or, in multicellular organisms, cancer. The purpose of this review is to discuss the known signal transduction pathways that regulate cell cycle progression and the mechanisms cells employ to insure DNA stability in the face of genotoxic stress. In particular, we focus on mammalian cell cycle checkpoint functions, their role in maintaining DNA stability during the cell cycle following exposure to genotoxic agents, and the gene products that act in checkpoint function signal transduction cascades. Key transitions in the cell cycle are regulated by the activities of various protein kinase complexes composed of cyclin and cyclin-dependent kinase (Cdk) molecules. Surveillance control mechanisms that check to ensure proper completion of early events and cellular integrity before initiation of subsequent events in cell cycle progression are referred to as cell cycle checkpoints and can generate a transient delay that provides the cell more time to repair damage before progressing to the next phase of the cycle. A variety of cellular responses are elicited that function in checkpoint signaling to inhibit cyclin/Cdk activities. These responses include the p53-dependent and p53-independent induction of Cdk inhibitors and the p53-independent inhibitory phosphorylation of Cdk molecules themselves. Eliciting proper G1, S, and G2 checkpoint responses to double-strand DNA breaks requires the function of the Ataxia telangiectasia mutated gene product. Several human heritable cancer-prone syndromes known to alter DNA stability have been found to have defects in checkpoint surveillance pathways. Exposures to several common sources of genotoxic stress, including oxidative stress, ionizing radiation, UV radiation, and the genotoxic compound benzo[a]pyrene, elicit cell cycle checkpoint responses that show both similarities and differences in their molecular signaling.

Animals↗
PubMed1998

Sensitivity of human prostatic carcinoma cell lines to low dose rate radiation exposure.

PURPOSE: Low dose rate radioemitters, such as 125I, 103Pd, and 89Sr, have been used both for local and systemic treatment of prostate cancer. Most normal cells exposed to ionizing radiation characteristically activate cell cycle checkpoints, resulting in cell cycle arrest at the G1/S and G2/M transition points. Cancer cells are typically quite sensitive to radiation killing late in the G2 phase of the replicative cell cycle. Furthermore, most cancer cells accumulating at the G2/M transition point as a result of low dose rate radiation exposure appear to become sensitive to further low dose rate irradiation. For this reason, protracted exposure of cancer cells to low dose rate radiation has been proposed to result in increased cancer cell killing as compared with brief exposures of cancer cells to high dose rate radiation. Since many human prostatic carcinomas contain somatic genome alterations targeting genes which affect the cell cycle and radiation-associated cell cycle checkpoints, we evaluated the effects of low dose rate radiation exposure on the cell cycle and on clonogenic survival for various human prostatic carcinoma cell lines. MATERIALS AND METHODS: Human prostatic carcinoma cells from the LNCaP, DU 145, PC-3, PPC-1, and TSU-Pr1 cell lines were exposed to low dose rate (0.25 Gy/hour) or high dose rate (60 Gy/hour) radiation in vitro and then assessed for radiation cytotoxicity by clonogenic survival assay. Cell cycle perturbations following protracted exposure to low dose rate radiation were evaluated using flow cytometry. RESULTS: For LNCaP cells, low dose rate radiation exposure resulted in an accumulation of cells at both the G1/S and the G2/M cell cycle transition points. For DU 145, PC-3, PPC-1, and TSU-Pr1 cells, treatment with low dose rate radiation triggered G2/M cell cycle arrest, but not G1/S arrest. Unexpectedly, the cell cycle redistribution pattern phenotypes observed, G1/S and G2/M cell cycle arrest versus G2/M arrest alone, appeared to have little effect on low dose rate radiation survival. Furthermore, while PC-3, PPC-1, and TSU-Pr1 cells exhibited increased cytotoxic sensitivity to low dose rate versus fractionated high dose rate radiation treatment, DU 145 and LNCaP cells did not. CONCLUSIONS: Radiation-associated pertubations in replicative cell cycle progression were not dominant determinants of low dose rate radiation killing efficacy in human prostate cancer cell lines in vitro.

Humans↗
PubMed2000

Apoptosis and cell cycle: distinct checkpoints with overlapping upstream control.

The question as to whether apoptosis (programmed cell death) is controlled by one or few checkpoints is still unresolved. A growing body of evidence suggests that (one of) the decisive event(s) of cell death consists in the permeabilization of mitochondrial membranes. Indeed, multiple pro-apopotic signal transduction pathways converge on the proteins of the Bcl-2/Bax family which, in concert with the so-called permeability transition pore complex (PTPC), regulate mitochondrial membrane barrier function. Mitochondrial permeabilization causes the release of soluble intermembrane proteins, some of which are involved in the activation of apoptotic proteases and nucleases. Thus, the putative checkpoint determining the death/life decision is clearly different from the known checkpoints of cell cycle progression. Prominent oncogenes (e.g., c-Myc, Ras, Raf, Bcl-2) and tumor suppressor genes (e.g., p53, Bax) have been shown to modulate apoptosis via a direct or indirect effect on mitochondrial membranes. All these oncoproteins and tumor suppressor proteins may simultaneously influence the cell cycle and the propensity to undergo apoptosis. Several cell cycle regulatory proteins (e.g., cyclins, cdk, etc.) can induce or inhibit apoptosis via yet unknown pathways.

Animals↗
PubMed2001

DNA damage-dependent and -independent phosphorylation of the hRad9 checkpoint protein.

Cell cycle checkpoints are regulatory mechanisms that maintain genomic integrity by preventing cell cycle progression when genetic anomalies are present. The hRad9 protein is the human homologue of Schizosaccharomyces pombe Rad9, a checkpoint protein required for preventing the onset of mitosis if DNA damage is present or if DNA replication is incomplete. Genetic and biochemical analyses indicate that hRad9 is a component of the checkpoint response in humans and has possible roles in regulating the cell cycle, apoptosis, and DNA repair. Previous studies indicate that hRad9 is modified by phosphorylation, both in the absence of exogenous stress and in response to various genotoxins. In this study, we report the mapping of several sites of constitutive phosphorylation of hRad9 to (S/T)PX(R/P) sequences near the C terminus of the protein. We also demonstrate that a serine to alanine mutation at residue 272 abrogates an ionizing radiation (IR)-induced phosphorylation of hRad9 and further show that phosphorylation at (S/T)P sites is not a prerequisite for IR-induced phosphorylation of serine 272. Finally, we report that hRad9 undergoes cell cycle-regulated hyper-phosphorylation in G(2)/M that is enhanced by IR but distinct from that on serine 272. Unlike the IR-induced phosphorylation at serine 272, this event is dependent on serine 277 and threonine 292, two C-terminal (S/T)P sites in hRad9.

Cell Cycle↗
PubMed1999

Potent inhibition of tumor survival in vivo by beta-lapachone plus taxol: combining drugs imposes different artificial checkpoints.

Ablation of tumor colonies was seen in a wide spectrum of human carcinoma cells in culture after treatment with the combination of beta-lapachone and taxol, two low molecular mass compounds. They synergistically induced death of cultured ovarian, breast, prostate, melanoma, lung, colon, and pancreatic cancer cells. This synergism is schedule dependent; namely, taxol must be added either simultaneously or after beta-lapachone. This combination therapy has unusually potent antitumor activity against human ovarian and prostate tumor prexenografted in mice. There is little host toxicity. Cells can commit to apoptosis at cell-cycle checkpoints, a mechanism that eliminates defective cells to ensure the integrity of the genome. We hypothesize that when cells are treated simultaneously with drugs activating more than one different cell-cycle checkpoint, the production of conflicting regulatory signaling molecules induces apoptosis in cancer cells. beta-Lapachone causes cell-cycle delays in late G(1) and S phase, and taxol arrests cells at G(2)/M. Cells treated with both drugs were delayed at multiple checkpoints before committing to apoptosis. Our findings suggest an avenue for developing anticancer therapy by exploiting apoptosis-prone "collisions" at cell-cycle checkpoints.

Animals↗
PubMed1993

Loss of a p53-associated G1 checkpoint does not decrease cell survival following DNA damage.

Cell cycle checkpoints regulate progression through the cell cycle. In yeast, loss of the G2 checkpoint by mutation of the rad9 gene results in increased genetic instability as well as increased sensitivity to ionizing radiation. In contrast, comparing clonogenic survival of cells which are isogeneic except for p53 functional status, we find that loss of a G1 checkpoint in mammalian cells is not associated with increased sensitivity to the lethal effects of ionizing radiation or a topoisomerase I inhibitor, camptothecin. These results indicate that increased sensitivity to DNA-damaging agents is not necessarily a defining feature of a mammalian cell cycle checkpoint. Furthermore, in light of a recent link of p53 function to radiation-induced apoptosis in hematopoietic cells, these observations suggest that p53-dependent apoptosis is a cell type-specific phenomenon and thus predict that the biological consequences of loss of p53 function will be cell type specific.

Camptothecin↗
PubMed2001

Inhibition of Chk1-dependent G2 DNA damage checkpoint radiosensitizes p53 mutant human cells.

Cell cycle checkpoints are surveillance mechanisms that monitor and coordinate the order and fidelity of cell cycle events. When defects in the division program of a cell are detected, checkpoints prevent the pursuant cell cycle transition through regulation of the relevant cyclin-cdk complex(es). Checkpoints that respond to DNA damage have been described for the G1, S and G2 phases of the cell cycle. The p53 tumour suppressor is a key regulator of G1/S checkpoints, and can promote cell cycle delay or apoptosis in response to DNA damage. The importance of these events to cellular physiology is highlighted by the fact that tumours, in which p53 is frequently mutated, have widespread defects in the G1/S DNA damage checkpoints and a heightened level of genomic instability. G2/M DNA damage checkpoints have been defined by yeast genetics, though the genes in this response are conserved in mammals. We show here using biochemical and physiological assays that p53 is dispensable for a DNA damage checkpoint activated in the G2 phase of the cell cycle. Moreover, upregulation of p53 through serine 20 phosphorylation, does not occur in G2. Conversely, we show that the Chk1 protein kinase is essential for the human G2 DNA damage checkpoint. Importantly, inhibition of Chk1 in p53 deficient cells greatly sensitizes them to radiation, validating the hypothesis of targeting Chk1 in rational drug design and development for anti-cancer therapies.

Blotting, Western↗
PubMed1997

The Drosophila grapes gene is related to checkpoint gene chk1/rad27 and is required for late syncytial division fidelity.

BACKGROUND: Cell cycle checkpoints maintain the fidelity of the somatic cell cycle by ensuring that one step in the cell cycle is not initiated until a previous step has been completed. The extent to which cell cycle checkpoints play a role in the initial rapid embryonic divisions of higher eukaryotes is unclear. The initial syncytial divisions of Drosophila embryogenesis provide an excellent opportunity to address this issue as they are amenable to both genetic and cellular analysis. In order to study the relevance of cell cycle checkpoints in early Drosophila embryogenesis, we have characterized the maternal-effect grapes (grp) mutation, which may affect feedback control during early syncytial divisions. RESULTS: The Drosophila grp gene encodes a predicted serine/threonine kinase and has significant homology to chk1/rad27, a gene required for a DNA damage checkpoint in Schizosaccharomyces pombe. Relative to normal embryos, embryos derived from grp-mutant mothers exhibit elevated levels of DNA damage. During nuclear cycles 12 and 13, alignment of the chromosomes on the metaphase plate was disrupted in grp-derived embryos, and the embryos underwent a progression of cytological events that were indistinguishable from those observed in normal syncytial embryos exposed to X-irradiation. The mutant embryos also failed to progress through a regulatory transition in Cdc2 activity that normally occurs during interphase of nuclear cycle 14. CONCLUSION: We propose that the primary defect in grp-derived embryos is a failure to replicate or repair DNA completely before mitotic entry during the late syncytial divisions. This suggests that wild-type grp functions in a developmentally regulated DNA replication/damage checkpoint operating during the late syncytial divisions. These results are discussed with respect to the proposed function of the chk1/rad27 gene.

Amino Acid Sequence↗
PubMed1998

Molecular analyses of adaptive survival responses (ASRs): role of ASRs in radiotherapy.

Adaptive survival responses (ASRs), whereby cells demonstrate a survival advantage when exposed to very low doses of ionizing radiation (IR) 4 - 24 h prior to a high dose challenge, were first reported over 15 years ago. These responses were linked to hormesis, which implied that exposure to low levels of IR may be beneficial to the cell. We postulate that increased survival does not necessarily mean that the treatment is beneficial. Studies at the molecular level indicate that ASRs are the result of misregulated cell cycle checkpoint responses, occurring in the G1 phase of the cell cycle after IR. Specific gene products (i.e., PCNA, cyclin D1, cyclin A, XIP8, xip5 and xip13) appear to control these cell cycle checkpoint responses. Certain neoplastic cells show potent ASRs because they bypass checkpoints which would otherwise lead to apoptosis or other forms of cell death (possibly necrosis), and/or these cancer cells lack genetic factors, such as specific caspases (cysteine aspartate-specific proteases), that control apoptosis. Alterations in these cell cycle checkpoints or apoptotic responses may also occur during IR-induced stress responses in normal cells, at critical times (10-18 days posttreatment) following IR. One IR-induced protein, XIP8, may be a critical controlling factor at this point where delayed-onset apoptosis occurs. Additionally, we have shown that the presence or absence (i.e., SCID cells) of nonhomologous DNA double strand break repair did not seem to influence ASRs, suggesting that ASRs may be caused by signal transduction stress responses. ASRs may be beneficial to survival, however, the consequence(s) of that survival may be dire. For example, many neoplastic cells exhibited far greater ASRs than normal cells. Additionally, ASRs were induced by as little as 1 cGy and and were enhanced by repeated exposures of low level radiation. The implications for radiotherapy are that when a patient arrives for port film imaging during the course of therapy, the dose-rate, overall level of exposure, and time between port film exposure and high dose IR treatment become potentially important factors for improved efficacy of treatment of certain cancers. Further research is warranted to determine what molecular factors are most important for ASRs, and current work is focusing on XIP8.

Adaptation, Physiological↗
PubMed1999

ATM: the protein encoded by the gene mutated in the radiosensitive syndrome ataxia-telangiectasia.

PURPOSE: To provide an update on the product of the ATM gene mutated in the human genetic disorder ataxia-telangiectasia (A-T). SUMMARY: The product of the ATM gene mutated in the human genetic disorder A-T is a 350 kDa protein that plays a central role in the regulation of a number of cellular processes. It is a member of the phosphatidylinositol 3-kinase superfamily, but is more likely a protein kinase similar to another member of that family, i.e. DNA-dependent protein kinase (DNA-PK). A-T cells and fibroblasts derived from the atm -/- mouse are hypersensitive to ionizing radiation and defective in cell cycle checkpoint control. At present the nature of the lesion in damaged DNA recognized by ATM remains uncertain, but it is evident that a small number of residual strand breaks remain unrepaired in A-T cells, which may well account for the radiosensitivity. On the other hand, considerable progress has been achieved in delineating the role of ATM in cell cycle checkpoint control. Defects are observed at all cell cycle checkpoints in A-T cells post-irradiation. At the G1 /S interface ATM has been shown to play a central role in radiation-induced activation of the tumour suppressor gene product p53. ATM binds to p53 in a complex fashion and activates the molecule in response to breaks in DNA by phosphorylating it at serine 15 close to the N-terminus and by controlling other phosphorylation and dephosphorylation changes on the molecule. This in turn leads to the induction of p21/WAF1 and other p53 effector proteins before inhibition of cyclin-dependent kinase activity and G1 arrest. Emerging evidence supports a direct role for ATM at other cell cycle checkpoints. Other proteins interacting with ATM include c-Abl a protein tyrosine kinase, beta-adaptin an endosomal protein and p21 a downstream effector of p53. The significance of these interactions is currently being investigated. ATM also plays an important role in the regulation and surveillance of meiotic progression. The localization of ATM to both the nucleus and other subcellular organelles implicates this molecule in a myriad of cellular processes. CONCLUSION: ATM is involved in DNA damage recognition and cell cycle control in response to ionizing radiation damage. There is evidence that ATM may also have a more general signalling role.

Animals↗
PubMed1997

Fragments of ATM which have dominant-negative or complementing activity.

The ATM protein has been implicated in pathways controlling cell cycle checkpoints, radiosensitivity, genetic instability, and aging. Expression of ATM fragments containing a leucine zipper motif in a human tumor cell line abrogated the S-phase checkpoint after ionizing irradiation and enhanced radiosensitivity and chromosomal breakage. These fragments did not abrogate irradiation-induced G1 or G2 checkpoints, suggesting that cell cycle checkpoint defects alone cannot account for chromosomal instability in ataxia telangiectasia (AT) cells. Expression of the carboxy-terminal portion of ATM, which contains the PI-3 kinase domain, complemented radiosensitivity and the S-phase checkpoint and reduced chromosomal breakage after irradiation in AT cells. These observations suggest that ATM function is dependent on interactions with itself or other proteins through the leucine zipper region and that the PI-3 kinase domain contains much of the significant activity of ATM.

Ataxia Telangiectasia↗