Proneness to UV-induced apoptosis in human fibroblasts defective in transcription coupled repair is associated with the lack of Mdm2 transactivation

Conforti, G; Nardò, Tiziana; D’Incalci, Maurizio; Stefanini, Miria

doi:10.1038/sj.onc.1203583

Cited by 48 publications

(25 citation statements)

References 43 publications

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“…18 The results presented here confirm and extend these observations by showing that it is the 90/92 kDa Mdm2 isoform that accumulate preferentially in wild-type and XP-C fibroblasts, but not in CS-B cells ( Figure 5). Mdm2 also fails to accumulate post-UV in CS-A and XP-A cells, implying that this response is related to an inability to carry out TC-NER.…”

Section: P53 and Mdm2 Changes In Xpg-deficient Fibroblastssupporting

confidence: 85%

“…Mdm2 also fails to accumulate post-UV in CS-A and XP-A cells, implying that this response is related to an inability to carry out TC-NER. 18,26 However, as shown here, not all TC-NER defective cells respond to UV irradiation in the same way. MDM2 transcripts, particularly those from the P2 promoter, fail to accumulate in XPG-deficient cells post-UV treatment whereas they do accumulate, albeit later than normal, in CS-A and CS-B cells (Figure 6).…”

Section: P53 and Mdm2 Changes In Xpg-deficient Fibroblastsmentioning

confidence: 50%

“…The higher apoptotic levels found in CS-A, CS-B and XP-A cells (Figure 1) support the corollary, namely that UV-induced apoptosis is somehow related to defective TC-NER. 11,16,18,27,28 XP-G fibroblasts, which are severely impaired in both NER and TC-NER, respond to UV like XP-A cells (Figure 1). Their behaviour is thus consistent with these propositions.…”

Section: Discussion Apoptosis In Xpg-deficient Fibroblastsmentioning

confidence: 99%

“…This is consistent with much earlier work suggesting that apoptosis levels correlate better with the persistence of unrepaired lesions in transcribed DNA. 11,[16][17][18] Clearly, it will be of interest to examine the XP-G and XP-G/CS cells for potential differences in TC-NER and/or transcription. For the moment, the important novel conclusion is that the exquisite sensitivity of XP-G/CS cells to UV-induced apoptosis is not simply due to their retention of more DNA damage than other repairdeficient cells.…”

Section: Apoptosis Levels Do Not Simply Correlate With the Extent Of mentioning

confidence: 99%

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Suppression of UV-induced apoptosis by the human DNA repair protein XPG

Clément¹,

Dunand-Sauthier²,

Sg³

2005

Cell Death Differ

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The severe xeroderma pigmentosum/Cockayne syndrome (XP/CS) syndrome is caused by mutations in the XPB, XPD and XPG genes that encode the helicase subunits of TFIIH and the 3 0 endonuclease of nucleotide excision repair (NER). Because XPB and XPD have been implicated in p53-mediated apoptosis, we examined the possible involvement of XPG in this process. After ultraviolet light (UV) irradiation, primary fibroblasts of XP complementation group G (XP-G) individuals with CS enter apoptosis more readily than other NER-deficient cells, but this is unlinked to unrepaired damage. These XP-G/ CS cells accumulate p53 post-UV but they fail to accumulate the 90/92 kDa isoforms of Mdm2 and their cellular distribution of Mdm2 is impaired. Apoptosis levels revert to wild type, Mdm2 90/92 kDa isoforms accumulate, and Mdm2 regains its normal post-UV nuclear location in transduced XP-G/CS cells expressing wild-type XPG, but not an XPG catalytic site mutant. These results suggest that XPG suppresses UVinduced apoptosis and that this suppression, most simply, requires its endonuclease function.

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Section: P53 and Mdm2 Changes In Xpg-deficient Fibroblastssupporting

confidence: 85%

Section: P53 and Mdm2 Changes In Xpg-deficient Fibroblastsmentioning

confidence: 50%

Section: Discussion Apoptosis In Xpg-deficient Fibroblastsmentioning

confidence: 99%

Section: Apoptosis Levels Do Not Simply Correlate With the Extent Of mentioning

confidence: 99%

See 2 more Smart Citations

Suppression of UV-induced apoptosis by the human DNA repair protein XPG

Clément¹,

Dunand-Sauthier²,

Sg³

2005

Cell Death Differ

View full text Add to dashboard Cite

show abstract

“…Defects in TCR result in clinical diseases such as Cockayne's Syndrome (CS) and Xeroderma Pigmentosa complementation group A (XP-A). CS and XP-A patients, in addition to their other clinical manifestations, exhibit hypersensitivity to UV radiation (Conforti et al, 2000). In addition, these cells are unable to recover mRNA synthesis following UV radiation and, correspondingly, have a low threshold for UV radiation-induced apoptosis (Ljungman and Zhang, 1996).…”

Section: Introductionmentioning

confidence: 99%

Lack of functional pRb results in attenuated recovery of mRNA synthesis and increased apoptosis following UV radiation in human breast cancer cells

et al. 2002

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Lack of functional pRb results in attenuated recovery of mRNA synthesis and increased apoptosis following UV radiation in human breast cancer cells. We have previously demonstrated that a human breast cancer cell line, MDA-MB-468, which lacks the retinoblastoma protein (pRb), is particularly sensitive to low doses of ultraviolet (UV) radiation. These cells are 15 ± 20-fold more sensitive to UV radiation than cells with wild-type pRb. In order to understand the mechanisms of the high apoptotic response of MDA-MB-468 cells to UV radiation, we examined the e ects of UV on these cells with regards to both membrane-mediated events and DNA damage. We found that MDA-MB-468 cells were resistant to all ligandinduced death receptor signaling. In addition, although UV activated caspase 8 in MDA-MB-468 cells, a peptide inhibitor of caspase 8 failed to inhibit UV-induced apoptosis. We then tested the possibility that nuclear events mediated the enhanced sensitivity to UV-induced apoptosis in these cells. Unlike UV-resistant cells, MDA-MB-468 cells were unable to recover mRNA synthesis after 5 J/m 2 UVC. We also found that the pRb-null DU-145 cells similarly had attenuated recovery of mRNA synthesis after UV radiation. In UV-resistant cells with wild-type pRb, the inactivation of pRb with HPV-16 E7 resulted in signi®cant inhibition in their ability to recover mRNA synthesis and increased levels of apoptosis following UV radiation. Furthermore, pRb-null cells were de®cient in repair of UV radiation-induced DNA damage. These data suggest that the sensitivity of MDA-MB-468 cells to UV radiation is due to defects in repair of DNA damage and recovery of mRNA synthesis rather than to membrane death receptor pathways. Inactivation of pRb may contribute to an increased sensitivity to UV radiation by attenuating repair of DNA lesions and recovery of mRNA synthesis following UV radiation.

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Nucleotide Excision Repair and its Connection with Cancer and Ageing

Andressoo

Hoeijmakers

Waard

Genome Instability in Cancer Development

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Proneness to UV-induced apoptosis in human fibroblasts defective in transcription coupled repair is associated with the lack of Mdm2 transactivation

Cited by 48 publications

References 43 publications

Suppression of UV-induced apoptosis by the human DNA repair protein XPG

Suppression of UV-induced apoptosis by the human DNA repair protein XPG

Lack of functional pRb results in attenuated recovery of mRNA synthesis and increased apoptosis following UV radiation in human breast cancer cells

Nucleotide Excision Repair and its Connection with Cancer and Ageing

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