ATM-dependent expression of IEX-1 controls nuclear accumulation of Mcl-1 and the DNA damage response

Abstract

The early-response gene product IEX-1 (also known as IER3) was recently found to interact with the anti-apoptotic Bcl-2 family member, myeloid cell leukemia-1 (Mcl-1). In this study we show that this interaction specifically and timely controls the accumulation of Mcl-1 in the nucleus in response to DNA damage. The IEX-1 protein is rapidly induced by γ-irradiation, genotoxic agents or replication inhibitors, in a way dependent on ataxia telangiectasia mutated (ATM) activity and is necessary for Mcl-1 nuclear translocation. Conversely, IEX-1 protein proteasomal degradation triggers the return of Mcl-1 to the cytosol. IEX-1 and Mcl-1 are integral components of the DNA damage response. Loss of IEX-1 or Mcl-1 leads to genomic instability and increased sensitivity to genotoxic and replicative stresses. The two proteins cooperate to maintain Chk1 activation and G2 checkpoint arrest. Mcl-1 nuclear translocation may foster checkpoint and improve the tumor resistance to DNA damage-based cancer therapies. Deciphering the pathways involved in IEX-1 degradation should lead to the discovery of new therapeutic targets to increase sensitivity of tumor cells to chemotherapy.

Comprehensive identification of genes driven by ERV9-LTRs reveals TNFRSF10B as a re-activatable mediator of testicular cancer cell death

“…48 Similar functions in inflammation and/or cell death may apply to additional ERV9-LTR-driven genes, such as CCR4, NR1H4 and PTPN13. In gastric cancer, TNFα leads to aberrant chemokine receptor CCR4 expression, which then suppresses immune reactions against the cancer cells, a phenomenon known as tumor-induced immunosuppression.…”

Nucleoporin NUP153 guards genome integrity by promoting nuclear import of 53BP1

“…From a wider perspective, our findings of the 53BP1-NUP153/importin-b pathway as an important aspect of the DDR network add to an emerging evidence of subcellular trafficking as an integral part of genome surveillance. Such evidence encompasses ATM-regulated nuclear export 29 and import, 30 as well as the import of essential genome caretakers, such as the FANCD2, RAD51 or BRCA1 repair proteins, [31][32][33] ribonucleotide reductases, 34 DNA damageregulated transcription factors, 35 the ATM-activator protein Aven 36 or p53 tumor suppressor. 37 Although our overall understanding of the role(s) for mammalian NUPs and NPCs in genome maintenance is still in its infancy, significant advances in this research area have already been made based on experiments with yeast models.…”

Thrombopoietin promotes NHEJ DNA repair in hematopoietic stem cells through specific activation of Erk and NF-κB pathways and their target, IEX-1

“…24,[27][28][29][30][31] We have recently reported a role of IEX-1 in the DNA-damage response. 32 We show here that upon IR, TPO, but not other cytokines, induces IEX-1 expression in hematopoietic stem and progenitor cells (HSPCs) through its unique ability to trigger sustained Erk and nuclear factor kB (NF-kB) activation. IEX-1 then connects specifically TPO/Mplinduced phosphorylated Erks to DNA-PK when DNA damage occurs.…”

“…37 Removal of TPO from the medium led to a striking decrease in total pErk1/2 levels ( Figure 2A The early gene IEX-1/IER3 was previously found to regulate DNA damage responses upon IR. 32 In addition, we have identified the IEX-1 protein as an Erk substrate involved in TPO-mediated function in megakaryocytes, 24,25 suggesting that it could play a role in TPO/Erk signaling-mediated DNA repair in HSPCs. Compatible with this possibility, the Iex-1 messenger RNA (mRNA) expression pattern follows that of Mpl, increasing greatly in HSC-enriched populations ( Figure 3A).…”