Role for KAP1 Serine 824 Phosphorylation and Sumoylation/Desumoylation Switch in Regulating KAP1-mediated Transcriptional Repression *
Journal of Biological Chemistry, ISSN: 0021-9258, Vol: 282, Issue: 50, Page: 36177-36189
2007
- 145Citations
- 143Captures
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Metrics Details
- Citations145
- Citation Indexes145
- 145
- CrossRef121
- Captures143
- Readers143
- 143
Article Description
As a multifunctional protein, KRAB domain-associated protein 1 (KAP1) is reportedly subjected to multiple protein posttranslational modifications, including phosphorylation and sumoylation. However, gaps exist in our knowledge of how KAP1 phosphorylation cross-talks with KAP1 sumoylation and what the biological consequence is. Here, we show that doxorubicin (Dox) treatment induces KAP1 phosphorylation at Ser-824 via an ataxia telangiectasia mutated (ATM)-dependent manner, correlating with the transcriptional de-repression of p21 WAF1/CIP1 and Gadd45α. A S824A substitution of KAP1, which ablates the ATM-induced phosphorylation, results in an increase of KAP1 sumoylation and repression of p21 transcription in Dox-treated cells. By contrast, a S824D mutation of KAP1, which mimics constitutive phosphorylation of KAP1, leads to a decrease of KAP1 sumoylation and stimulation of p21 transcription before the exposure of Dox. We further provide evidence that SENP1 deSUMOylase is involved in activating basal, but not Dox-induced, KAP1 Ser-824 phosphorylation, rendering a stimulation of p21 and Gadd45α transcription. Moreover, KAP1 and differential sumoylation of KAP1 were also demonstrated to fine-tune the transcription of three additional KAP1-targeted genes, including Bax, Puma, and Noxa. Taken together, our results suggest a novel role for ATM that selectively stimulates KAP1 Ser-824 phosphorylation to repress its sumoylation, leading to the de-repression of expression of a subset of genes involved in promoting cell cycle control and apoptosis in response to genotoxic stresses.
Bibliographic Details
http://www.sciencedirect.com/science/article/pii/S0021925818460681; http://dx.doi.org/10.1074/jbc.m706912200; http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=37549021501&origin=inward; http://www.ncbi.nlm.nih.gov/pubmed/17942393; http://www.jbc.org/lookup/doi/10.1074/jbc.M706912200; https://syndication.highwire.org/content/doi/10.1074/jbc.M706912200; https://linkinghub.elsevier.com/retrieve/pii/S0021925818460681; https://dx.doi.org/10.1074/jbc.m706912200
American Society for Biochemistry & Molecular Biology (ASBMB)
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