The roles of Wnt signaling in genome stability
Our work demonstrated that basal Wnt signaling is required for faithful execution of mitosis. In the first funding period, we found that Wnt signaling controls chromosome segregation in mitosis by two specific mechanisms. First, we found that Wnt signaling promotes chromosome congression in mitosis by recruiting the mitotic kinesin KIF2A to the spindle. Second, we demonstrated that Wnt10b-dependent auto/paracrine signaling is required during S-phase to maintain proper microtubule dynamics and to ensure faithful chromosome segregation in the subsequent mitosis. Additional experiments have shown that inhibition of Wnt signaling reduces the progression of DNA replication and increases replication origin firing in S-phase, which leads to whole chromosome missegregation and aneuploidy. Additionally, our experiments also showed that Wnt signaling regulates chromosome segregation in self-renewing, but not in differentiating stem cells. Thus, we hypothesize that Wnt signaling provides a key layer of control for genome stability in somatic as well as in stem cells to ensure genome maintenance during development and tissue renewal. Here, we propose to characterize the mechanisms underlying Wnt10b regulation of DNA replication in S-phase and mitosis, and to determine how Wnt signaling impacts genome stability in stem cells. We will investigate how Wnt10b-mediated control of DNA replication relates to the regulation of mitotic microtubule dynamics and chromosome segregation. We will also define the specific Wnt10b-dependent signaling pathway that is involved in the regulation of intra-S-phase events. Importantly, since abnormalities during DNA replication can cause structural chromosome aberrations, we will address the question whether and how Wnt signaling ensures genome integrity, both on a structural and numerical chromosome level. To further explore the biological relevance of these processes, we will analyze how Wnt signaling regulates genome integrity in mouse embryonic stem cells and in blastocysts. In these models, we will assess whether loss of Wnt signaling promotes defects in S-phase (DNA replication) or directly in M-phase (KIF2A), and which Wnt(s) are dedicated to each process. Finally, we will characterize the bi-directional relationship between Wnt-dependent genomic maintenance and self-renewal of stem cells.
- Bufe, A., A. García del Arco, M.I. Hennecke, A. de Jaime-Soguero, M. Ostermaier, Y.C. Lin, A. Ciprianidis, U. Engel, P. Beli, H. Bastians and S.P. Acebrón‡. 2020. Wnt signaling recruits KIF2A to the spindle to ensure chromosome congression and alignment during mitosis. PNAS. 118(34):e2108145118. PMID: 34417301
- Giebel, N., A. de Jaime-Soguero, A. García del Arco, J.J.M. Landry, M. Tietje, L. Villacorta, V. Benes, V. Fernández-Saiz, and S.P. Acebrón ‡. 2020. USP42 protects ZNRF3/RNF43 from R-spondin-dependent clearance and inhibits Wnt signalling. EMBO Reports 5;22(5):e51415. PMID: 33786993
- Lin, YC., A. Haas, A. Bufe, S. Parbin, M. Hennecke, O. Voloshanenko, J. Gross, M. Boutros, S.P. Acebrón, and H. Bastians. 2020. Wnt10b-GSK3β-dependent Wnt/STOP signaling prevents aneuploidy in human somatic cells. Life Science Alliance. 4(1):e202000855. PMID: 33257473
- Schmidt, AK., K. Pudelko, J.E. Boekenkamp, K. Berger, M. Kschischo, and H. Bastians. 2020. The p53/p73 - p21CIP1 tumor suppressor axis guards against chromosomal instability by restraining CDK1 in human cancer cells. Oncogene. Published online ahead of print. PMID: 33168930.
- Bohly, N., M. Kistner, and H. Bastians. 2019. Mild replication stress causes aneuploidy by deregulating microtubule dynamics in mitosis. Cell Cycle. 18:2770-2783. PMID: 31448675.
- Berger, B.S.*, S.P. Acebrón#,*, J. Herbst, S. Koch and C. Niehrs. 2017. Parkinson associated receptor GPR37 is an ER chaperone for LRP6. EMBO Rep. 18(5):712-725. PMID: 28341812
- Koch, S.*, S.P. Acebrón*, J. Herbst, G. Hatiboglu, and C. Niehrs. 2015. Post-transcriptional Wnt Signaling Governs Epididymal Sperm Maturation. Cell. 163:1225-1236. PMID: 26590424
- Huang, Y.L., Z. Anvarian, G. Doderlein, S.P. Acebrón#, and C. Niehrs. 2015. Maternal Wnt/STOP signaling promotes cell division during early Xenopus embryogenesis. Proc Natl Acad Sci U S A. 112:5732-5737. PMID: 25901317
- Stolz, A., K. Neufeld, N. Ertych, and H. Bastians. 2015. Wnt-mediated protein stabilization ensures proper mitotic microtubule assembly and chromosome segregation. EMBO Rep. 16:490-499. PMID: 25656539.
- Acebrón, S.P.#, E. Karaulanov, B.S. Berger, Y.L. Huang, and C. Niehrs. 2014. Mitotic wnt signaling promotes protein stabilization and regulates cell size. Mol Cell. 54:663-674. PMID: 24837680
- Ertych, N., A. Stolz, A. Stenzinger, W. Weichert, S. Kaulfuss, P. Burfeind, A. Aigner, L. Wordeman, and H. Bastians. 2014. Increased microtubule assembly rates influence chromosomal instability in colorectal cancer cells. Nature Cell Biol. 16:779-791. PMID: 24976383.
(* equal contribution, # Joint corresponding authorship)