Defects in transcription coupled repair interfere with expression of p90MDM2 in response to ultraviolet light

Michalowski, Jennifer; Seavey, Scott E.; Mendrysa, Susan M.; Perry, Mary Ellen

doi:10.1038/sj.onc.1204721

Cited by 5 publications

(4 citation statements)

References 44 publications

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“…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%

“…25,26 To determine the potential effect of transcriptional regulation on Mdm2 protein accumulation, we examined by quantitative real-time PCR the steady-state levels of the P1 and P2 transcripts at various times post-UV, using the primers and exon junction TaqMan probes indicated in Figure 6a.…”

Section: Mdm2 Transcripts Are Made In Reduced Amounts In Tc-ner Defecmentioning

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 Fibroblastsmentioning

confidence: 50%

Section: Mdm2 Transcripts Are Made In Reduced Amounts In Tc-ner Defecmentioning

confidence: 99%

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

Clément¹,

Dunand-Sauthier²,

Sg³

2005

Cell Death Differ

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“…Our MDM2 mRNA analysis does not discriminate between transcripts from two MDM2 promoters, reflecting p53-independent and p53-responsive mRNA accumulation, respectively (11). However, in contrast to transcripts from the human gene, both promoter transcripts from the mouse gene can be induced by DNA-damaging agents and have been shown to support MDM2 protein accumulation (37,38). It is thus possible that the increased MDM2 mRNA levels resulted in increased protein synthesis, but that a rapid turnover of MDM2 prevented increasing protein levels.…”

Section: Rt±pcr and Ishmentioning

confidence: 70%

Characterizing the role of MDM2 in diethylnitrosamine induced acute liver damage and development of pre-neoplastic lesions

Finnberg

Silins²,

Stenius³

et al. 2003

Carcinogenesis

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Pre-neoplastic lesions in rodent liver often express high levels of MDM2 and lack a p53 response to DNA damage. The question we posed was whether there is a liver-specific regulation of the p53/MDM2 feedback loop and if it can be related to the development of pre-neoplastic lesions, referred to as enzyme altered foci (EAF) in rats. Acute responses of p53 and MDM2 to diethylnitrosamine (DEN) were characterized by employing immunohistochemistry, western blotting, RT-PCR and in situ hybridization. A single dose of DEN induced a centrilobular p53 response that peaked at 24 h. It was associated with transcriptional activation of MDM2 and signs of apoptosis. However, in midzonal hepatocytes, which constitutively expressed high levels of cytoplasmic MDM2, there was a rapid-onset but transient p53 response. It was terminated at 24 h and there were no signs of apoptosis. The rapidly declining p53 levels in midzonal areas was preceded by a transient peak in MDM2 mRNA levels at 6 h. Rats pre-treated with repeated low or high weekly doses of DEN exhibited EAF and these lesions expressed high levels of cytoplasmic MDM2. Using MDM2 as a marker for EAF gave similar results as using glutathione transferase-P (GST-P) as a marker. Furthermore, small EAF, elicited by low doses of DEN, were preferentially localized to midzonal areas. It is concluded that in centrilobular areas DEN-induced alterations in p53/MDM2 levels are compatible with a previously described feedback loop. An attenuated p53 response in midzonal hepatocytes can be related to a high constitutive expression of MDM2 in these cells. The localization of small EAF to midzonal areas, and the fact that EAF cells expressed high levels of MDM2, indicates that MDM2 expression is a factor governing initiation and early development of EAF. The data support the hypothesis that EAF hepatocytes are initiated via epigenetic mechanisms.

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“…Investigations of HCT-116 MLH1 -deficient cells have revealed hypersensitivity to UV light due to dysfunction of TC-NER, while artificially introduction of MLH1 gene to this cell line leads to TC-NER system activity and hence reduced sensitivity to UV light [54], [56]. It has also been reported that dysfunction of TC-NER system down-regulates transcription of particular genes [57]. These observations suggest that there may be a similar MLH1 mechanism of action on the regulation of FXN transcription.…”

Section: Discussionmentioning

confidence: 99%

MutLα Heterodimers Modify the Molecular Phenotype of Friedreich Ataxia

Ezzatizadeh

Sandi

et al. 2014

PLoS ONE

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BackgroundFriedreich ataxia (FRDA), the most common autosomal recessive ataxia disorder, is caused by a dynamic GAA repeat expansion mutation within intron 1 of FXN gene, resulting in down-regulation of frataxin expression. Studies of cell and mouse models have revealed a role for the mismatch repair (MMR) MutS-heterodimer complexes and the PMS2 component of the MutLα complex in the dynamics of intergenerational and somatic GAA repeat expansions: MSH2, MSH3 and MSH6 promote GAA repeat expansions, while PMS2 inhibits GAA repeat expansions.Methodology/Principal FindingsTo determine the potential role of the other component of the MutLα complex, MLH1, in GAA repeat instability in FRDA, we have analyzed intergenerational and somatic GAA repeat expansions from FXN transgenic mice that have been crossed with Mlh1 deficient mice. We find that loss of Mlh1 activity reduces both intergenerational and somatic GAA repeat expansions. However, we also find that loss of either Mlh1 or Pms2 reduces FXN transcription, suggesting different mechanisms of action for Mlh1 and Pms2 on GAA repeat expansion dynamics and regulation of FXN transcription.Conclusions/SignificanceBoth MutLα components, PMS2 and MLH1, have now been shown to modify the molecular phenotype of FRDA. We propose that upregulation of MLH1 or PMS2 could be potential FRDA therapeutic approaches to increase FXN transcription.

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Defects in transcription coupled repair interfere with expression of p90MDM2 in response to ultraviolet light

Cited by 5 publications

References 44 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

Characterizing the role of MDM2 in diethylnitrosamine induced acute liver damage and development of pre-neoplastic lesions

MutLα Heterodimers Modify the Molecular Phenotype of Friedreich Ataxia

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