title: ATM mediates pRB function to control DNMT1 protein stability and DNA methylation.
abstract: 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 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 promoters of at least the Ink4a, Shc2, FoxO6, and Noggin genes. Furthermore, we demonstrate that inactivation of pRB promotes 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 the pRB pathway in coordination with aberration in the DNA damage response deregulates DNMT1 stability, leading to an abnormal DNA methylation pattern and malignant progression.
authors.affiliation: Division of Oncology and Molecular Biology, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Awad
authors.initials: A
authors.lastname: Shamma
authors.forename: Misa
authors.initials: M
authors.lastname: Suzuki
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Hayashi
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Nobunari
authors.initials: N
authors.lastname: Sasaki
authors.forename: Takumi
authors.initials: T
authors.lastname: Nishiuchi
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
authors.forename: Takahiro
authors.initials: T
authors.lastname: Okamoto
authors.forename: Susumu
authors.initials: S
authors.lastname: Kohno
authors.forename: Hayato
authors.initials: H
authors.lastname: Muranaka
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kitajima
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Chiaki
authors.initials: C
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004795:Enzyme Stability; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013961:Thyroid Gland / Q000378:metabolism / Q000473:pathology*; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases