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| Status |
Public on May 31, 2013 |
| Title |
ATM mediates pRB function to control DNMT1 protein stability and DNA methylation |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
|
| Summary |
The retinoblastoma tumor suppressor gene (RB) product has been implicated in epigenetic control of gene expression owing to its ability to physically bind to many of chromatin modifiers. However, the biological and clinical significance of this activity was not well elucidated. To address this, we performed genetic and epigenetic analyses in an Rb-deficient mouse thyroid C cell tumor model. Here we report that the genetic interaction of Rb and ATM regulates DNMT1 protein stability, and hence controls the DNA methylation status in the promoter of at least Ink4a, Shc2, FoxO6 and Noggin genes. Further, we demonstrate that inactivation of pRB promotes the Tip60 (acetyltransferase)-dependent ATM activation, allows activated ATM to physically bind to DNMT1 forming a complex with Tip60 and UHRF1 (E3 ligase), and consequently accelerates DNMT1 ubiquitination driven by Tip60-dependent acetylation. Our results indicate that inactivation of pRB pathway in coordination with aberration in DNA damage response leads to abnormal DNA methylation pattern by affecting the stability of DNMT1.
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| Overall design |
163; Rb-/-;ATM-/- MEFs, D4; DNMT1 knockdown from 163 cells and analysed at day 4, WT8S; 163 cells reconstituted with ATM expression vector
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| Contributor(s) |
Shamma A, Nishiuchi T, Takahashi C |
| Citation(s) |
23754744 |
| |
| Submission date |
May 30, 2013 |
| Last update date |
Jan 19, 2018 |
| Contact name |
Awad Shamma |
| E-mail(s) |
shamawad@staff.kanazawa-u.ac.jp
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| Phone |
+81-76-264-6751
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| Fax |
+81-76-234-4521
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| URL |
http://omb.w3.kanazawa-u.ac.jp/omb/Home.html
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| Organization name |
Kanazawa Uiniversity
|
| Department |
Cancer Research Institute
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| Lab |
Division of Oncology and Molecular Biology
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| Street address |
Kakuma-machi
|
| City |
Kanazawa |
| State/province |
Ishikawa |
| ZIP/Postal code |
920-1192 |
| Country |
Japan |
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| Platforms (1) |
| GPL10333 |
Agilent-026655 Whole Mouse Genome Microarray 4x44K v2 (Feature Number version) |
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| Samples (3) |
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| Relations |
| BioProject |
PRJNA205897 |
