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Nucleic Acids Res ; 52(12): 6945-6963, 2024 Jul 08.
Article in English | MEDLINE | ID: mdl-38783095

ABSTRACT

Cellular senescence, a major driver of aging, can be stimulated by DNA damage, and is counteracted by the DNA repair machinery. Here we show that in p16INK4a-deficient cells, senescence induction by the environmental genotoxin B[a]P or ionizing radiation (IR) completely depends on p21CIP1. Immunoprecipitation-based mass spectrometry interactomics data revealed that during senescence induction and maintenance, p21CIP1 specifically inhibits CDK4 and thereby activates the DREAM complex. Genome-wide transcriptomics revealed striking similarities in the response induced by B[a]P and IR. Among the top 100 repressed genes 78 were identical between B[a]P and IR and 76 were DREAM targets. The DREAM complex transcriptionally silences the main proliferation-associated transcription factors E2F1, FOXM1 and B-Myb as well as multiple DNA repair factors. Knockdown of p21CIP1, E2F4 or E2F5 diminished both, repression of these factors and senescence. The transcriptional profiles evoked by B[a]P and IR largely overlapped with the profile induced by pharmacological CDK4 inhibition, further illustrating the role of CDK4 inhibition in genotoxic stress-induced senescence. Moreover, data obtained by live-cell time-lapse microscopy suggest the inhibition of CDK4 by p21CIP1 is especially important for arresting cells which slip through mitosis. Overall, we identified the p21CIP1/CDK4/DREAM axis as a master regulator of genotoxic stress-induced senescence.


Subject(s)
Cellular Senescence , Cyclin-Dependent Kinase 4 , Cyclin-Dependent Kinase Inhibitor p21 , DNA Damage , Kv Channel-Interacting Proteins , Cellular Senescence/radiation effects , Cellular Senescence/genetics , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Cyclin-Dependent Kinase Inhibitor p21/genetics , Cyclin-Dependent Kinase 4/metabolism , Cyclin-Dependent Kinase 4/genetics , Humans , Kv Channel-Interacting Proteins/metabolism , Kv Channel-Interacting Proteins/genetics , Radiation, Ionizing , DNA Repair , Gene Expression Regulation/radiation effects , Repressor Proteins
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