DNA damage-induced cell death by apoptosis

Roos, Wynand P.; Kaina, Bernd

doi:10.1016/j.molmed.2006.07.007

Cited by 1,304 publications

(1,040 citation statements)

References 82 publications

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“…30 Apoptosis induced by O 6 MeG was shown to require DNA replication 24 and MutSa-mediated formation of DSBs 27 that trigger either the mitochondrial or the death receptor apoptotic pathway. 31 Here, we show that upon the induction of O 6 MeG and under MGMT-depleted conditions, H2AX becomes phosphorylated in ES (R1) cells, which is indicative of the formation of DSBs. 32 Further, ES cells showed a higher level of nuclear p53 in response to MNNG, compared to fibroblasts.…”

Section: Discussionmentioning

confidence: 60%

Mouse embryonic stem cells are hypersensitive to apoptosis triggered by the DNA damage O6-methylguanine due to high E2F1 regulated mismatch repair

Roos¹,

Christmann²,

Fraser

et al. 2007

Cell Death Differ

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Exposure of stem cells to genotoxins may lead to embryonic lethality or teratogenic effects. This can be prevented by efficient DNA repair or by eliminating genetically damaged cells. Using undifferentiated mouse embryonic stem (ES) cells as a pluripotent model system, we compared ES cells with differentiated cells, with regard to apoptosis induction by alkylating agents forming the highly mutagenic and killing DNA adduct O 6 -methylguanine. Upon treatment with N-methyl-N 0 -nitro-N-nitrosoguanidine (MNNG), ES cells undergo apoptosis at much higher frequency than differentiated cells, although they express a high level of the repair protein O 6 -methylguanine-DNA methyltransferase (MGMT). Apoptosis induced by MNNG is due to O 6 -methylguanine DNA adducts, since inhibition of MGMT sensitized ES cells. The high sensitivity of ES cells to O 6 -methylating agents is due to high expression of the mismatch repair proteins MSH2 and MSH6 (MutSa), which declines during differentiation. High MutSa expression in ES cells was related to a high hyperphosphorylated retinoblastoma (ppRb) level and E2F1 activity that upregulates MSH2, causing, in turn, stabilization of MSH6. Non-repaired O 6 -methylguanine adducts were shown to cause DNA doublestranded breaks, stabilization of p53 and upregulation of Fas/CD95/Apo-1 at significantly higher level in ES cells than in fibroblasts. The high apoptotic response of ES cells to O 6 -methylguanine adducts may contribute to reduction of the mutational load in the progenitor population.

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Section: Discussionmentioning

confidence: 60%

Mouse embryonic stem cells are hypersensitive to apoptosis triggered by the DNA damage O6-methylguanine due to high E2F1 regulated mismatch repair

Roos¹,

Christmann²,

Fraser

et al. 2007

Cell Death Differ

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“…Different types of DNA damage exist that lead to the generation of various DNA alterations, such as cyclobutane pyrimidine dimers, oxidized bases, singlestrand breaks or double-strand breaks (DSBs) (reviewed in Sancar et al, 2004;Roos and Kaina, 2006). The latter, which can be induced by topoisomerase inhibitors as well as IR, are extremely toxic and can lead to chromosomal aberrations and genetic instability (van Gent et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…Several genes upregulated by p53 target the mitochondria to induce the release of cytochrome c, Smac/DIABLO and other mediators of apoptosis. These include Bad, Bax, PUMA and Noxa (for a recent review, see Roos and Kaina, 2006). Furthermore, caspase-2 has been shown to be activated by PIDD and to act upstream of the mitochondria by promoting mitochondrial membrane permeabilization (Guo et al, 2002;Lassus et al, 2002;Robertson et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

p53-induced protein with a death domain (PIDD) isoforms differentially activate nuclear factor-kappaB and caspase-2 in response to genotoxic stress

et al. 2007

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Cellsres pond to DNA damage in a complex way and the fate of damaged cells depends on the balance between pro-and antiapoptotic signals. This is of crucial importance in cancer as genotoxic stress is implied both in oncogenesis and in classical tumor therapies. p53-induced protein with a death domain (PIDD), initially described as a p53-inducible gene, is one of the molecular switches able to activate a survival or apoptotic program. Two isoforms of PIDD, PIDD ( isoform 1) and LRDD ( isoform 2), have already been reported and we describe here a third isoform. These three isoforms are differentially expressed in tissues and cell lines. Genotoxic stress only affects PIDD isoform 3 mRNA levels, whereas isoforms 1 and 2 mRNA levels remain unchanged. All isoforms are capable of activating nuclear factor-kappaB in response to genotoxic stress, but only isoform 1 interacts with RIP-associated ICH-1/CED-3 homologous protein with a death domain and activates caspase-2. Isoform 2 counteracts the pro-apoptotic function of isoform 1, whereas isoform 3 enhances it. Thus, the differential splicing of PIDD mRNA leads to the formation of at least three proteins with antagonizing/agonizing functions, thereby regulating cell fate in response to DNA damage

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“…The culture conditions are crucial for favoring cell adhesion, proliferation, and differentiation. Apart from the nutrient limitation, a primary cause of cell death during the stationary and death phase of the growth (Mercille and Massie 1994), a particularly important aspect is the accumulation of toxic waste products both from endogenous and from exogenous sources over time, which leads to the induction of DNA damage, formation of DNA lesions, and then premature apoptotic cell death (Al-Rubeai and Singh 1998;Kaina 2003;Roos and Kaina 2006).…”

Section: Introductionmentioning

confidence: 99%

“…However, in most cases, DNA damage arises from exogenous sources, such as ultraviolet (UV) light from the sun, ionizing radiation, and numerous environmental chemicals (Roos and Kaina 2006). If these lesions cannot be repaired in time or damaged DNAs are incorrectly repaired, it could lead to serious consequences.…”

Section: Introductionmentioning

confidence: 99%

Comparative proteomics analysis of global cellular stress responses to hydroxyurea-induced DNA damage in HeLa cells

et al. 2014

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Both environmental agents and spontaneous cellular events cause serious DNA damage, threatening the integrity of the genome. In response to replication stress or genotoxic agents triggered DNA damage, degradation of p12 subunit of DNA polymerase delta (Pol d) results in an inter-conversion between heterotetramer (Pol d4) and heterotrimer (Pol d3) forms and plays a significant role in DNA damage response in eukaryotic cells. In this work, we used mass spectrometry-based proteomic approach to identify those cellular stress response protein changes corresponding to the degradation of p12 in DNAdamaged HeLa cells by the treatment with hydroxyurea (HU). A total of 736 ± 13 proteins in non-treated control group and 741 ± 19 protein spots in HUtreated cells were detected, of which 34 proteins (17 up-regulated and 17 down-regulated) exhibited significantly altered protein expression levels. Their physiological roles are mainly associated with cellular components, molecular functions, and biological processes by gene ontology analysis, among which 21 proteins were mapped to KEGG pathways. They are involved in 5 primary pathways with the subsets involving 16 secondary pathways by further KEGG analysis. More interestingly, the up-regulation of translationally controlled tumor protein was further identified to be associated with p12 degradation by Western blot analysis. Our works may enlarge and broaden our view for deeply understanding how global cellular stress responds to DNA damage, which could contribute to the etiology of human cancer or other diseases that can result from loss of genomic stability.

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DNA damage-induced cell death by apoptosis

Cited by 1,304 publications

References 82 publications

Mouse embryonic stem cells are hypersensitive to apoptosis triggered by the DNA damage O6-methylguanine due to high E2F1 regulated mismatch repair

Mouse embryonic stem cells are hypersensitive to apoptosis triggered by the DNA damage O6-methylguanine due to high E2F1 regulated mismatch repair

p53-induced protein with a death domain (PIDD) isoforms differentially activate nuclear factor-kappaB and caspase-2 in response to genotoxic stress

Comparative proteomics analysis of global cellular stress responses to hydroxyurea-induced DNA damage in HeLa cells

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