Blood Journal
Leading the way in experimental and clinical research in hematology

ATM regulates a DNA damage response posttranscriptional RNA operon in lymphocytes

  1. Krystyna Mazan-Mamczarz1,
  2. Patrick R. Hagner1,
  3. Yongqing Zhang2,
  4. Bojie Dai1,
  5. Elin Lehrmann2,
  6. Kevin G. Becker2,
  7. Jack D. Keene3,
  8. Myriam Gorospe4,
  9. Zhenqui Liu1, and
  10. Ronald B. Gartenhaus1,5,6
  1. 1Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, MD;
  2. 2Gene Expression and Genomics Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD;
  3. 3Department of Molecular Genetics & Microbiology, Duke University Medical Center, Durham, NC;
  4. 4Laboratory of Cellular and Molecular Biology, National Institute on Aging, National Institutes of Health, Baltimore, MD;
  5. 5Department of Medicine, University of Maryland Medical School, Baltimore, MD; and
  6. 6Veterans Administration Medical Center, Baltimore, MD

Abstract

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.

  • Submitted September 30, 2010.
  • Accepted December 30, 2010.
View Full Text