Biology subjects

Willenbrock, M.

Publications and source records attributed to Willenbrock, M..

2 recordsLinked to original sources

bioRxiv2023

A computational model of the DNA damage-induced IKK/ NF-κB pathway reveals a critical dependence on irradiation dose and PARP-1

The activation of IKK/ NF-{kappa}B by genotoxic stress is a crucial process in the DNA damage response. Due to the anti-apoptotic impact of NF-{kappa}B it can affect cell fate decisions upon DNA damage and therefore interfere with tumour therapy-induced cell death. Here, we developed a dynamical model describing IKK/ NF-{kappa}B signalling that faithfully reproduces quantitative time course data and enabled a detailed analysis of pathway regulation. The approach elucidates a pathway topology with two hubs, where the first integrates signals from two DNA damage sensors and the second forms a coherent feedforward loop. The analyses reveal a critical role of the sensor protein PARP-1 in the pathway regulation. Introducing a method for calculating the impact of individual components on pathway activity in a time-resolved manner we show how irradiation dose influences pathway activation. Our results give a mechanistic understanding relevant for the interpretation of experimental and clinical studies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/538686v1_ufig1.gif" ALT="Figure 1"> View larger version (75K): org.highwire.dtl.DTLVardef@5ba82borg.highwire.dtl.DTLVardef@17dc530org.highwire.dtl.DTLVardef@1cf6fborg.highwire.dtl.DTLVardef@19ae207_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2019

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

The I{kappa}B kinase (IKK) - NF-{kappa}B 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-{kappa}B 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 I{kappa}B and is terminated through I{kappa}B (NFKBIA) re-expression. 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 GSK3{beta}, results in transcriptional silencing of NFKBIA and IKK-independent, constitutive activation of NF-{kappa}B in senescence. Collectively, our study reveals a novel physiological mechanism of NF-{kappa}B activation with important implications for genotoxic cancer treatment.

cell biology↗