Reactome | DNA Damage/Telomere Stress Induced Senescence

DNA Damage/Telomere Stress Induced Senescence

Stable Identifier

R-HSA-2559586

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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DNA Damage/Telomere Stress Induced Senescence

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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.

Literature References

PubMed ID	Title	Journal	Year
15790808	ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex Paull, TT, Lee, JH	Science	2005
9357549	Reactive oxygen species-induced DNA damage and its modification: a chemical investigation Anderson, D, Yu, TW	Mutat. Res.	1997
15574587	Smurf2 up-regulation activates telomere-dependent senescence Cohen, SN, Zhang, H	Genes Dev.	2004
8242752	WAF1, a potential mediator of p53 tumor suppression. Tokino, T, el-Deiry, WS, Kinzler, KW, Vogelstein, B, Lin, D, Mercer, WE, Parsons, R, Trent, JM, Velculescu, VE, Levy, DB	Cell	1993
9843217	ATM associates with and phosphorylates p53: mapping the region of interaction. Gatei, M, Hobson, K, Taya, Y, Kozlov, S, Scott, S, Keating, KE, Lees-Miller, SP, Lavin, MF, Gabrielli, B, Khanna, KK, Chan, D	Nat Genet	1998
10669743	Control of human telomere length by TRF1 and TRF2 van Steensel, B, Schnapp, G, Schaefer, MR, Oelmann, S, Smogorzewska, A, de Lange, T, Bianchi, A	Mol. Cell. Biol.	2000
9733514	Enhanced phosphorylation of p53 by ATM in response to DNA damage. Shiloh, Y, Taya, Y, Reiss, Y, Ziv, Y, Smorodinsky, NI, Prives, C, Anderson, CW, Chessa, L, Moyal, L, Shieh, S, Banin, S	Science	1998
2342578	Telomeres shorten during ageing of human fibroblasts Greider, CW, Futcher, AB, Harley, CB	Nature	1990
19528227	Mitochondrial dysfunction contributes to oncogene-induced senescence Ferbeyre, G, Deschênes-Simard, X, Roux, A, Bourdeau, V, Moiseeva, O	Mol. Cell. Biol.	2009
8242751	The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Keyomarsi, K, Elledge, SJ, Adami, GR, Wei, N, Harper, JW	Cell	1993
9733515	Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Appella, E, Siliciano, JD, Kastan, MB, Tamai, K, Taya, Y, Sakaguchi, K, Lim, DS, Canman, CE	Science	1998
10037601	p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2 Karlseder, J, Broccoli, D, Hardy, S, Dai, Y, de Lange, T	Science	1999
16166375	Shelterin: the protein complex that shapes and safeguards human telomeres de Lange, T	Genes Dev	2005
2392154	Telomere reduction in human colorectal carcinoma and with ageing Dempster, M, Thompson, AM, Dunlop, MG, Allshire, RC, Green, DK, Hastie, ND	Nature	1990
17694070	MRE11-RAD50-NBS1 and ATM function as co-mediators of TRF1 in telomere length control Xiao, S, Wu, Y, Zhu, XD	Nat. Struct. Mol. Biol.	2007