ATM and IRAK1 orchestrate two distinct mechanisms of NF-κB activation in response to DNA damage

Elodie Bournique; Ambrocio Sanchez; Sunwoo Oh; Daniel Ghazarian; Alisa L Mahieu; Lavanya Manjunath; Eirene Ednacot; Pedro Ortega; Selma Masri; Ivan Marazzi; Rémi Buisson

doi:10.1038/s41594-024-01417-0

ATM and IRAK1 orchestrate two distinct mechanisms of NF-κB activation in response to DNA damage

Nat Struct Mol Biol. 2025 Jan 3. doi: 10.1038/s41594-024-01417-0. Online ahead of print.

Authors

Elodie Bournique^{1

2

3}, Ambrocio Sanchez^{1

2

3}, Sunwoo Oh^{1

2

3}, Daniel Ghazarian^{1

2

3}, Alisa L Mahieu^{1

2}, Lavanya Manjunath^{1

2

3}, Eirene Ednacot^{1

2

4}, Pedro Ortega^{1

2

3}, Selma Masri^{1

2}, Ivan Marazzi^{1

2

3}, Rémi Buisson^{5

6

7

8}

Affiliations

¹ Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA.
² Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA.
³ Center for Virus Research, University of California Irvine, Irvine, CA, USA.
⁴ Department of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical Sciences, University of California Irvine, Irvine, CA, USA.
⁵ Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA. [email protected].
⁶ Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA. [email protected].
⁷ Center for Virus Research, University of California Irvine, Irvine, CA, USA. [email protected].
⁸ Department of Pharmaceutical Sciences, School of Pharmacy & Pharmaceutical Sciences, University of California Irvine, Irvine, CA, USA. [email protected].

PMID: 39753776
DOI: 10.1038/s41594-024-01417-0

Abstract

DNA damage in cells induces the expression of inflammatory genes. However, the mechanism by which cells initiate an innate immune response in the presence of DNA lesions blocking transcription remains unknown. Here we find that genotoxic stresses lead to an acute activation of the transcription factor NF-κB through two distinct pathways, each triggered by different types of DNA lesions and coordinated by either ataxia-telangiectasia mutated (ATM) or IRAK1 kinases. ATM stimulates NF-κB in cells with DNA double-strand breaks. By contrast, IRAK1-induced NF-κB signaling occurs in neighboring cells through IL-1α secretion from transcriptionally stressed cells caused by DNA lesions blocking RNA polymerases. Subsequently, both pathways stimulate TRAF6 and the IKK complex to promote NF-κB-mediated inflammatory gene expression. These findings provide an alternative mechanism for damaged cells with impaired transcription to initiate an inflammatory response without relying on their own gene expression, a necessary step that injured cells depend on during canonical innate immune responses.