A novel IKK- and proteasome-independent mechanism of RelA activation triggers senescence associated secretome via transcriptional repression of NFKBIA

Item Type:

Preprint

Title:

Creators Name:

Kolesnichenko, M. and Mikuda, N. and Höpken, U.E. and Milanovic, M. and Tufan, A.B. and Uyar, B. and Sun, W. and Schleich, K. and von Hoff, L. and Willenbrock, M. and Krahn, I. and Jungmann, S. and Hinz, M. and Akalin, A. and Lee, S. and Schmidt-Ullrich, R. and Schmitt, C.A. and Scheidereit, C.

Abstract:

The IκB kinase (IKK) - NF-κB pathway is activated as part of the DNA damage response and controls both resistance to apoptosis and inflammation. How these different 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 first, rapidly activated phase is driven by the ATM-PARP1-TRAF6-IKK cascade, which triggers proteasomal destruction of IκBα and is terminated through IκBα (NFKBIA) reexpression. The second phase is activated days later in senescent cells but is independent of IKK and the proteasome. An altered phosphorylation status of p65, in part driven by GSK3β, results in transcriptional silencing of NFKBIA and IKKindependent, 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.

Keywords:

Senescence, NF-κB, IκBα, SASP, DNA Damage Response, Cancer Therapy

Source:

bioRxiv

Publisher:

Cold Spring Harbor Laboratory Press

Article Number:

2019.12.19.882225

Date:

20 December 2019

Official Publication:

https://doi.org/10.1101/2019.12.19.882225

Related to:

URL	URL Type
https://edoc.mdc-berlin.de/19866/	Final version

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