| First Author | Kolesnichenko M | Year | 2021 |
| Journal | EMBO J | Volume | 40 |
| Issue | 6 | Pages | e104296 |
| PubMed ID | 33459422 | Mgi Jnum | J:313630 |
| Mgi Id | MGI:6790035 | Doi | 10.15252/embj.2019104296 |
| Citation | Kolesnichenko M, et al. (2021) Transcriptional repression of NFKBIA triggers constitutive IKK- and proteasome-independent p65/RelA activation in senescence. EMBO J 40(6):e104296 |
| abstractText | The IkappaB kinase (IKK)-NF-kappaB 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-kappaB 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 IkappaBalpha, and is terminated through IkappaBalpha 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-kappaB family member p65/RelA, in part mediated by GSK3beta, results in transcriptional silencing of NFKBIA and IKK-independent, constitutive activation of NF-kappaB in senescence. Collectively, our study reveals a novel physiological mechanism of NF-kappaB activation with important implications for genotoxic cancer treatment. |
