Pathway
DNA Damage/Telomere Stress Induced Senescence
Reactive oxygen species (ROS), whose concentration increases in senescent cells due to oncogenic RAS-induced mitochondrial dysfunction or due to environmental stress, cause DNA damage in the form of double strand breaks (DSBs). In addition, persistent cell division fueled by oncogenic signaling leads to replicative exhaustion, manifested in critically short telomeres. Shortened telomeres are no longer able to bind the protective shelterin complex (Smogorzewska et al. 2000, de Lange 2005) and are recognized as damaged DNA.
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The evolutionarily conserved MRN complex, consisting of MRE11A (MRE11), RAD50 and NBN (NBS1) subunits, binds DSBs and shortened telomeres that are no longer protected by shelterin. Once bound to the DNA, the MRN complex recruits and activates ATM kinase, leading to phosphorylation of ATM targets, including TP53 (p53). TP53, phosphorylated on serine S15 by ATM, binds the CDKN1A (also known as p21, CIP1 or WAF1) promoter and induces CDKN1A transcription. CDKN1A inhibits the activity of CDK2, leading to G1/S cell cycle arrest.
SMURF2 is upregulated in response to telomere attrition in human fibroblasts and induces senecscent phenotype through RB1 and TP53, independently of its role in TGF-beta-1 signaling. The exact mechanism of SMURF2 involvement is senescence has not been elucidated.
REACT:R-HSA-2559586Reactome
What the reference databases state
Statements
58 statements
58 statements · 1 reference database · Subject: DNA Damage/Telomere Stress Induced Senescence · Sources: Reactome
- ACD participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- ASF1A participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- ATM participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- CABIN1 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- CCNA1 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- CCNA2 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- CCNE1 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- CCNE2 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- CDK2 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- CDKN1A participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- CDKN1B participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- EP400 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
Show the remaining 46
- H1-0 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- H1-1 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- H1-2 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- H1-3 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- H1-4 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- H1-5 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- H2AB1 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- H2AC14 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- H2AC18; H2AC19 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- H2AC20 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- H2AC4; H2AC8 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- H2AC6 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- H2AC7 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- H2AJ participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- H2AX participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- H2AZ2 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- H2BC1 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- H2BC11 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- H2BC12 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- H2BC13 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- H2BC14 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- H2BC15 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- H2BC17 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- H2BC21 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- H2BC26 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- H2BC3 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- H2BC4; H2BC6; H2BC7; H2BC8; H2BC10 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- H2BC9 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- H3-4 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- H4C1; H4C2; H4C3; H4C4; H4C5; H4C6; H4C8; H4C9; H4C11; H4C12; H4C13; H4C14; H4C15; H4C16 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- HIRA participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- HMGA1 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- HMGA2 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- KAT5 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- LMNB1 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- MRE11 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- NBN participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- POT1 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- RAD50 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- RB1 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- TERF1 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- TERF2 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- TERF2IP participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- TINF2 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- TP53 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only
- UBN1 participates in DNA Damage/Telomere Stress Induced SenescenceProteinReactome R-HSA-2559586Inferred only