Extra Centrosomes Delay DNA Damage-driven Tumorigenesis

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2024 Mar 29

PMID 38552015

Authors

Vincent Z Braun

Gerlinde Karbon

Fabian Schuler

Marina A Schapfl

Johannes G Weiss

Paul Y Petermann

Diana C J Spierings

Andrea E Tijhuis

Floris Foijer

Verena Labi

Andreas Villunger

Affiliations

Soon will be listed here.

Abstract

Deregulated centrosome numbers are frequently found in human cancer and can promote malignancies in model organisms. Current research aims to clarify if extra centrosomes are cause or consequence of malignant transformation, and if their biogenesis can be targeted for therapy. Here, we show that oncogene-driven blood cancer is inert to genetic manipulation of centrosome numbers, whereas the formation of DNA damage-induced malignancies is delayed. We provide first evidence that this unexpected phenomenon is connected to extra centrosomes eliciting a pro-death signal engaging the apoptotic machinery. Apoptosis induction requires the PIDDosome multi-protein complex, as it can be abrogated by loss of any of its three components, , , or . BCL2 overexpression equally blocks cell death, documenting for the first time induction of mitochondrial apoptosis downstream of extra centrosomes. Our findings demonstrate context-dependent effects of centrosome amplification during transformation and ask to adjust current belief that extra centrosomes are intrinsically pro-tumorigenic.

Citing Articles

Mitotic lethality prevents inflammation.

Zierhut C, Villunger A Nat Cell Biol. 2025; 27(1):7-8.

PMID: 39809996 DOI: 10.1038/s41556-024-01529-1.

STIL overexpression shortens lifespan and reduces tumor formation in mice.

Moussa A, Cosenza M, Wohlfromm T, Brobeil K, Hill A, Patrizi A PLoS Genet. 2024; 20(10):e1011460.

PMID: 39466849 PMC: 11542878. DOI: 10.1371/journal.pgen.1011460.

Stepwise phosphorylation and SUMOylation of PIDD1 drive PIDDosome assembly in response to DNA repair failure.

Shah R, Li Y, Yu H, Kini E, Sidi S Nat Commun. 2024; 15(1):9195.

PMID: 39448602 PMC: 11502896. DOI: 10.1038/s41467-024-53412-0.

Centrioles are frequently amplified in early B cell development but dispensable for humoral immunity.

Schapfl M, LoMastro G, Braun V, Hirai M, Levine M, Kiermaier E Nat Commun. 2024; 15(1):8890.

PMID: 39406735 PMC: 11480410. DOI: 10.1038/s41467-024-53222-4.

Amplified centrosomes-more than just a threat.

Kiermaier E, Stotzel I, Schapfl M, Villunger A EMBO Rep. 2024; 25(10):4153-4167.

PMID: 39285247 PMC: 11467336. DOI: 10.1038/s44319-024-00260-0.

References

Peel N, Stevens N, Basto R, Raff J . Overexpressing centriole-replication proteins in vivo induces centriole overduplication and de novo formation. Curr Biol. 2007; 17(10):834-43. PMC: 1885955. DOI: 10.1016/j.cub.2007.04.036. View

Redecke V, Wu R, Zhou J, Finkelstein D, Chaturvedi V, High A . Hematopoietic progenitor cell lines with myeloid and lymphoid potential. Nat Methods. 2013; 10(8):795-803. PMC: 4131762. DOI: 10.1038/nmeth.2510. View

Sladky V, Knapp K, Soratroi C, Heppke J, Eichin F, Rocamora-Reverte L . E2F-Family Members Engage the PIDDosome to Limit Hepatocyte Ploidy in Liver Development and Regeneration. Dev Cell. 2020; 52(3):335-349.e7. DOI: 10.1016/j.devcel.2019.12.016. View

Schneckenleithner C, Hoelbl-Kovacic A, Sexl V . Modeling BCR/ABL-driven malignancies in the mouse. Methods Mol Biol. 2015; 1267:263-82. DOI: 10.1007/978-1-4939-2297-0_12. View

Barna M, Pusic A, Zollo O, Costa M, Kondrashov N, Rego E . Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency. Nature. 2008; 456(7224):971-5. PMC: 2880952. DOI: 10.1038/nature07449. View

Bose A, Dalal S . Centrosome Amplification and Tumorigenesis: Cause or Effect?. Results Probl Cell Differ. 2019; 67:413-440. DOI: 10.1007/978-3-030-23173-6_18. View

Labi V, Erlacher M, Krumschnabel G, Manzl C, Tzankov A, Pinon J . Apoptosis of leukocytes triggered by acute DNA damage promotes lymphoma formation. Genes Dev. 2010; 24(15):1602-7. PMC: 2912557. DOI: 10.1101/gad.1940210. View

Srsen V, Merdes A . The centrosome and cell proliferation. Cell Div. 2006; 1:26. PMC: 1654144. DOI: 10.1186/1747-1028-1-26. View

Ohashi A, Ohori M, Iwai K, Nakayama Y, Nambu T, Morishita D . Aneuploidy generates proteotoxic stress and DNA damage concurrently with p53-mediated post-mitotic apoptosis in SAC-impaired cells. Nat Commun. 2015; 6:7668. PMC: 4506520. DOI: 10.1038/ncomms8668. View

10.

Bock F, Krumschnabel G, Manzl C, Peintner L, Tanzer M, Hermann-Kleiter N . Loss of PIDD limits NF-κB activation and cytokine production but not cell survival or transformation after DNA damage. Cell Death Differ. 2012; 20(4):546-57. PMC: 3595480. DOI: 10.1038/cdd.2012.152. View

11.

Shoshani O, Bakker B, de Haan L, Tijhuis A, Wang Y, Kim D . Transient genomic instability drives tumorigenesis through accelerated clonal evolution. Genes Dev. 2021; 35(15-16):1093-1108. PMC: 8336898. DOI: 10.1101/gad.348319.121. View

12.

Peintner L, Dorstyn L, Kumar S, Aneichyk T, Villunger A, Manzl C . The tumor-modulatory effects of Caspase-2 and Pidd1 do not require the scaffold protein Raidd. Cell Death Differ. 2015; 22(11):1803-11. PMC: 4648327. DOI: 10.1038/cdd.2015.31. View

13.

Vitre B, Holland A, Kulukian A, Shoshani O, Hirai M, Wang Y . Chronic centrosome amplification without tumorigenesis. Proc Natl Acad Sci U S A. 2015; 112(46):E6321-30. PMC: 4655534. DOI: 10.1073/pnas.1519388112. View

14.

Lin Y, Ma W, Benchimol S . Pidd, a new death-domain-containing protein, is induced by p53 and promotes apoptosis. Nat Genet. 2000; 26(1):122-7. DOI: 10.1038/79102. View

15.

Kwon Y, Ueda S, Ueno M, Yodoi J, Masutani H . Mechanism of p53-dependent apoptosis induced by 3-methylcholanthrene: involvement of p53 phosphorylation and p38 MAPK. J Biol Chem. 2001; 277(3):1837-44. DOI: 10.1074/jbc.M105033200. View

16.

Evans L, Anglen T, Scott P, Lukasik K, Loncarek J, Holland A . ANKRD26 recruits PIDD1 to centriolar distal appendages to activate the PIDDosome following centrosome amplification. EMBO J. 2020; 40(4):e105106. PMC: 7883295. DOI: 10.15252/embj.2020105106. View

17.

Garcia-Carpio I, Braun V, Weiler E, Leone M, Ninerola S, Barco A . Extra centrosomes induce PIDD1-mediated inflammation and immunosurveillance. EMBO J. 2023; 42(20):e113510. PMC: 10577638. DOI: 10.15252/embj.2023113510. View

18.

Kerketta L, Ghosh K, Nadkarni A, Madkaikar M, Vundinti B . Centrosome Aberration Frequency and Disease Association in B-Acute Lymphoblastic Leukemia. In Vivo. 2017; 31(2):215-220. PMC: 5411748. DOI: 10.21873/invivo.11048. View

19.

Fava L, Schuler F, Sladky V, Haschka M, Soratroi C, Eiterer L . The PIDDosome activates p53 in response to supernumerary centrosomes. Genes Dev. 2017; 31(1):34-45. PMC: 5287111. DOI: 10.1101/gad.289728.116. View

20.

Bonzon C, Bouchier-Hayes L, Pagliari L, Green D, Newmeyer D . Caspase-2-induced apoptosis requires bid cleavage: a physiological role for bid in heat shock-induced death. Mol Biol Cell. 2006; 17(5):2150-7. PMC: 1446087. DOI: 10.1091/mbc.e05-12-1107. View