ATM regulates a DNA damage response posttranscriptional RNA operon in lymphocytes.
Maintenance of genomic stability depends on the DNA damage response, a biologic barrier in early stages of cancer development. Failure of this response results in genomic instability and high predisposition toward lymphoma, as seen in patients with ataxia-telangiectasia mutated (ATM) dysfunction. ATM activates multiple cell-cycle checkpoints and DNA repair after DNA damage, but its influence on posttranscriptional gene expression has not been examined on a global level. We show that ionizing radiation modulates the dynamic association of the RNA-binding protein HuR with target mRNAs in an ATM-dependent manner, potentially coordinating the genotoxic response as an RNA operon. Pharmacologic ATM inhibition and use of ATM-null cells revealed a critical role for ATM in this process. Numerous mRNAs encoding cancer-related proteins were differentially associated with HuR depending on the functional state of ATM, in turn affecting expression of encoded proteins. The findings presented here reveal a previously unidentified role of ATM in controlling gene expression posttranscriptionally. Dysregulation of this DNA damage response RNA operon is probably relevant to lymphoma development in ataxia-telangiectasia persons. These novel RNA regulatory modules and genetic networks provide critical insight into the function of ATM in oncogenesis.
Duke Scholars
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- Tumor Suppressor Proteins
- Radiation, Ionizing
- RNA-Binding Proteins
- RNA, Messenger
- Protein Serine-Threonine Kinases
- Protein Binding
- Operon
- Mutant Proteins
- Lymphoma
- Lymphocytes
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Tumor Suppressor Proteins
- Radiation, Ionizing
- RNA-Binding Proteins
- RNA, Messenger
- Protein Serine-Threonine Kinases
- Protein Binding
- Operon
- Mutant Proteins
- Lymphoma
- Lymphocytes