ATM regulates a DNA damage response posttranscriptional RNA operon in lymphocytes

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.

A recently evolved class of alternative 3′-terminal exons involved in cell cycle regulation by topoisomerase inhibitors

“…6), and HuR can bind or affect the recruitment of splicing and polyadenylation factors to exons and polyA sites, respectively 39,41,42 . HuR dissociation from CENPN pre-mRNA in response to DOXO and CPT is consistent with ARTICLE previous evidence that HuR binding to RNA is affected by DNA damage [45][46][47] . HuR is phosphorylated by several protein kinases mediating DNA damage signalling, including Chk2, p38/MAPK, PKC and Cdk1 46 .…”

AU-rich RNA binding proteins in hematopoiesis and leukemogenesis

“…23 Finally, HuR have been implicated in posttranscriptional genotoxic/oxidative stress pathways in mammalian cells, 47 and recent data havew shown that it functions as a key mediator of the checkpoint kinase, ataxia telangiectasia mutated (ATM) in B lymphocyte cell lines. 48 In response to double-stranded DNA breaks, the ATM kinase phosphorylates a cascade of downstream effectors, including the checkpoint kinase CHK2, which in turn phosphorylates HUR to modulate its mRNA-binding and translational control functions. Ionizing radiation elicits a dramatic change in the profile of mRNAs that are associated with HUR in an ATM-dependent manner.…”

“…In each case, radiation-responsive up-regulation of their encoded proteins was mediated by translational control rather than by changes in mRNA levels. 48 Persons with the autosomal recessive ataxia telangiectasia (AT) condition who inherit defective ATM function are predisposed to develop lymphomas and lymphoid leukemias at high frequency. The ATM gene is also commonly mutated in sporadic lymphoid malignancies.…”

“…The ATM gene is also commonly mutated in sporadic lymphoid malignancies. Thus, HUR probably plays a key role in mediating the effects of loss of function of the ATM checkpoint kinase tumor suppressor in sporadic lymphoid malignancies as well as in AT patients 48 (Table 1).…”

Lymphocyte lineage-specific and developmental stage specific mechanisms suppress cyclin D3 expression in response to DNA double strand breaks

“…In response to DSBs induced by IR, ATM promotes phosphorylation of the HuR RNA binding protein to regulate association of HuR with its target mRNAs. 23 HuR functions in context-dependent manners to positively or negatively regulate stability and/or translation of its target mRNAs. 24 In primary human T cells, HuR binds and stabilizes Cyclin D3 mRNAs to enhance Cyclin D3 protein expression.…”