DNA Damage/Telomere Stress Induced Senescence

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Homo sapiens
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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
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, DeschĂȘnes-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
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
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
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