ATM regulates a DNA damage response posttranscriptional RNA operon in lymphocytes.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Mazan-Mamczarz, K; Hagner, PR; Zhang, Y; Dai, B; Lehrmann, E; Becker, KG; Keene, JD; Gorospe, M; Liu, Z; Gartenhaus, RB

Published Date

  • February 24, 2011

Published In

Volume / Issue

  • 117 / 8

Start / End Page

  • 2441 - 2450

PubMed ID

  • 21209379

Pubmed Central ID

  • 21209379

Electronic International Standard Serial Number (EISSN)

  • 1528-0020

Digital Object Identifier (DOI)

  • 10.1182/blood-2010-09-310987

Language

  • eng

Conference Location

  • United States