description
Reactive oxygen species (ROS), whose concentration increases in senescent cells due to oncogenic RAS-induced mitochondrial dysfunction (Moiseeva et al. 2009) or due to environmental stress, cause DNA damage in the form of double strand breaks (DSBs) (Yu and Anderson 1997). In addition, persistent cell division fueled by oncogenic signaling leads to replicative exhaustion, manifested in critically short telomeres (Harley et al. 1990, Hastie et al. 1990). 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. The evolutionarily conserved MRN complex, consisting of MRE11A (MRE11), RAD50 and NBN (NBS1) subunits, binds DSBs (Lee and Paull 2005) and shortened telomeres that are no longer protected by shelterin (Wu et al. 2007). Once bound to the DNA, the MRN complex recruits and activates ATM kinase (Lee and Paull 2005, Wu et al. 2007), leading to phosphorylation of ATM targets, including TP53 (p53) (Banin et al. 1998, Canman et al. 1998, Khanna et al. 1998). TP53, phosphorylated on serine S15 by ATM, binds the CDKN1A (also known as p21, CIP1 or WAF1) promoter and induces CDKN1A transcription (El-Deiry et al. 1993, Karlseder et al. 1999). CDKN1A inhibits the activity of CDK2, leading to G1/S cell cycle arrest (Harper et al. 1993, El-Deiry et al. 1993).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 (Zhang and Cohen 2004). The exact mechanism of SMURF2 involvement is senescence has not been elucidated

external resources
NCBI:1270429
REACTOME:R-HSA-2559586
PUBMED:15790808
PUBMED:15574587
PUBMED:10669743
PUBMED:9733515
PUBMED:9357549
PUBMED:8242751
PUBMED:17694070
PUBMED:2342578
PUBMED:9733514
PUBMED:10037601
PUBMED:2392154
PUBMED:9843217
PUBMED:19528227
PUBMED:16166375
PUBMED:8242752

genes
ATM , CCNA2 , CCNE1 , CDK2 , CDKN1A , CDKN1B , H1F0 , HIST1H1C , HIST1H1D , HIST1H1E , HIST1H1B , HIST1H2AE , HIST1H2AD , H2AFX , H2AFZ , HIST1H2BD , HIST1H2BB , HIST1H1A , HMGA1 , LMNB1 , MRE11 , NBN , RB1 , TERF1 , TERF2 , TP53 , HIRA , HMGA2 , HIST3H3 , HIST1H4I , HIST1H2AJ , HIST1H2AC , HIST1H2AB , HIST2H2AA3 , HIST2H2AC , HIST1H2BG , HIST1H2BL , HIST1H2BN , HIST1H2BM , HIST1H2BF , HIST1H2BE , HIST1H2BH , HIST1H2BI , HIST1H2BC , HIST1H2BO , HIST2H2BE , HIST1H4A , HIST1H4D , HIST1H4F , HIST1H4K , HIST1H4J , HIST1H4C , HIST1H4H , HIST1H4B , HIST1H4E , HIST1H4L , HIST2H4A , CCNA1 , HIST1H2BJ , CCNE2 , RAD50 , KAT5 , CABIN1 , ASF1A , POT1 , TINF2 , UBN1 , TERF2IP , H2AFJ , EP400 , ACD , HIST1H2BK , H2AFV , HIST4H4 , HIST3H2BB , HIST1H2BA , H2AFB1 , HIST2H4B , HIST2H2AA4 ,