Uncoupling of MTORC1 from E2F Activity Maintains DNA Damage and Senescence

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Oct 25

PMID 39448567

Authors

Leighton H Daigh

Debarya Saha

David L Rosenthal

Katherine R Ferrick

Tobias Meyer

Affiliations

Soon will be listed here.

Abstract

DNA damage is a primary trigger for cellular senescence, which in turn causes organismal aging and is a promising target of anti-aging therapies. Most DNA damage occurs when DNA is fragile during DNA replication in S phase, but senescent cells maintain DNA damage long-after DNA replication has stopped. How senescent cells induce DNA damage and why senescent cells fail to repair damaged DNA remain open questions. Here, we combine reversible expression of the senescence-inducing CDK4/6 inhibitory protein p16 (p16) with live single-cell analysis and show that sustained mTORC1 signaling triggers senescence in non-proliferating cells by increasing transcriptional DNA damage and inflammation signaling that persists after p16 is degraded. Strikingly, we show that activation of E2F transcriptional program, which is regulated by CDK4/6 activity and promotes expression of DNA repair proteins, repairs transcriptionally damaged DNA without requiring DNA replication. Together, our study suggests that senescence can be maintained by ongoing mTORC1-induced transcriptional DNA damage that cannot be sufficiently repaired without induction of protective E2F target genes.

References

Sousa-Victor P, Gutarra S, Garcia-Prat L, Rodriguez-Ubreva J, Ortet L, Ruiz-Bonilla V . Geriatric muscle stem cells switch reversible quiescence into senescence. Nature. 2014; 506(7488):316-21. DOI: 10.1038/nature13013. View

Kato D, Miyazawa K, Ruas M, Starborg M, Wada I, Oka T . Features of replicative senescence induced by direct addition of antennapedia-p16INK4A fusion protein to human diploid fibroblasts. FEBS Lett. 1998; 427(2):203-8. DOI: 10.1016/s0014-5793(98)00426-8. View

Fumagalli M, Rossiello F, Mondello C, dAdda di Fagagna F . Stable cellular senescence is associated with persistent DDR activation. PLoS One. 2014; 9(10):e110969. PMC: 4207795. DOI: 10.1371/journal.pone.0110969. View

Liu D, Greene L . Regulation of neuronal survival and death by E2F-dependent gene repression and derepression. Neuron. 2001; 32(3):425-38. DOI: 10.1016/s0896-6273(01)00495-0. View

Krenning L, Feringa F, Shaltiel I, van den Berg J, Medema R . Transient activation of p53 in G2 phase is sufficient to induce senescence. Mol Cell. 2014; 55(1):59-72. DOI: 10.1016/j.molcel.2014.05.007. View

Fingar D, Richardson C, Tee A, Cheatham L, Tsou C, Blenis J . mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol Cell Biol. 2003; 24(1):200-16. PMC: 303352. DOI: 10.1128/MCB.24.1.200-216.2004. View

Larsen D, Stucki M . Nucleolar responses to DNA double-strand breaks. Nucleic Acids Res. 2015; 44(2):538-44. PMC: 4737151. DOI: 10.1093/nar/gkv1312. View

Kent L, Bae S, Tsai S, Tang X, Srivastava A, Koivisto C . Dosage-dependent copy number gains in E2f1 and E2f3 drive hepatocellular carcinoma. J Clin Invest. 2017; 127(3):830-842. PMC: 5330731. DOI: 10.1172/JCI87583. View

Laberge R, Sun Y, Orjalo A, Patil C, Freund A, Zhou L . MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat Cell Biol. 2015; 17(8):1049-61. PMC: 4691706. DOI: 10.1038/ncb3195. View

10.

Moss T . At the crossroads of growth control; making ribosomal RNA. Curr Opin Genet Dev. 2004; 14(2):210-7. DOI: 10.1016/j.gde.2004.02.005. View

11.

McStay B, Grummt I . The epigenetics of rRNA genes: from molecular to chromosome biology. Annu Rev Cell Dev Biol. 2008; 24:131-57. DOI: 10.1146/annurev.cellbio.24.110707.175259. View

12.

Di Micco R, Fumagalli M, Cicalese A, Piccinin S, Gasparini P, Luise C . Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature. 2006; 444(7119):638-42. DOI: 10.1038/nature05327. View

13.

Leontieva O, Demidenko Z, Blagosklonny M . Dual mTORC1/C2 inhibitors suppress cellular geroconversion (a senescence program). Oncotarget. 2015; 6(27):23238-48. PMC: 4695114. DOI: 10.18632/oncotarget.4836. View

14.

Kang C, Xu Q, Martin T, Li M, Demaria M, Aron L . The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. Science. 2015; 349(6255):aaa5612. PMC: 4942138. DOI: 10.1126/science.aaa5612. View

15.

Chung M, Liu C, Yang H, Koberlin M, Cappell S, Meyer T . Transient Hysteresis in CDK4/6 Activity Underlies Passage of the Restriction Point in G1. Mol Cell. 2019; 76(4):562-573.e4. PMC: 7189330. DOI: 10.1016/j.molcel.2019.08.020. View

16.

Fumagalli M, Rossiello F, Clerici M, Barozzi S, Cittaro D, Kaplunov J . Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat Cell Biol. 2012; 14(4):355-65. PMC: 3717580. DOI: 10.1038/ncb2466. View

17.

Schwarz C, Johnson A, Koivomagi M, Zatulovskiy E, Kravitz C, Doncic A . A Precise Cdk Activity Threshold Determines Passage through the Restriction Point. Mol Cell. 2018; 69(2):253-264.e5. PMC: 5790185. DOI: 10.1016/j.molcel.2017.12.017. View

18.

Yang H, Wang H, Ren J, Chen Q, Chen Z . cGAS is essential for cellular senescence. Proc Natl Acad Sci U S A. 2017; 114(23):E4612-E4620. PMC: 5468617. DOI: 10.1073/pnas.1705499114. View

19.

Coller H, Sang L, Roberts J . A new description of cellular quiescence. PLoS Biol. 2006; 4(3):e83. PMC: 1393757. DOI: 10.1371/journal.pbio.0040083. View

20.

Ito T, Teo Y, Evans S, Neretti N, Sedivy J . Regulation of Cellular Senescence by Polycomb Chromatin Modifiers through Distinct DNA Damage- and Histone Methylation-Dependent Pathways. Cell Rep. 2018; 22(13):3480-3492. PMC: 5915310. DOI: 10.1016/j.celrep.2018.03.002. View