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Transcriptional repression of NFKBIA triggers constitutive IKK‐ and proteasome‐independent p65/RelA activation in senescence
Author(s) -
Kolesnichenko Marina,
Mikuda Nadine,
Höpken Uta E,
Kärgel Eva,
Uyar Bora,
Tufan Ahmet Bugra,
Milanovic Maja,
Sun Wei,
Krahn Inge,
Schleich Kolja,
Hoff Linda,
Hinz Michael,
Willenbrock Michael,
Jungmann Sabine,
Akalin Altuna,
Lee Soyoung,
SchmidtUllrich Ruth,
Schmitt Clemens A,
Scheidereit Claus
Publication year - 2021
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019104296
Subject(s) - biology , psychological repression , senescence , proteasome , iκb kinase , microbiology and biotechnology , nfkb1 , transcription factor , cancer research , genetics , signal transduction , nf κb , gene expression , gene
The IκB kinase (IKK)‐NF‐κB pathway is activated as part of the DNA damage response and controls both inflammation and resistance to apoptosis. How these distinct functions are achieved remained unknown. We demonstrate here that DNA double‐strand breaks elicit two subsequent phases of NF‐κB activation in vivo and in vitro, which are mechanistically and functionally distinct. RNA‐sequencing reveals that the first‐phase controls anti‐apoptotic gene expression, while the second drives expression of senescence‐associated secretory phenotype (SASP) genes. The rapidly activated first phase is driven by the ATM‐PARP1‐TRAF6‐IKK cascade, which triggers proteasomal destruction of inhibitory IκBα, and is terminated through IκBα re‐expression from the NFKBIA gene. The second phase, which is activated days later in senescent cells, is on the other hand independent of IKK and the proteasome. An altered phosphorylation status of NF‐κB family member p65/RelA, in part mediated by GSK3β, results in transcriptional silencing of NFKBIA and IKK‐independent, constitutive activation of NF‐κB in senescence. Collectively, our study reveals a novel physiological mechanism of NF‐κB activation with important implications for genotoxic cancer treatment.