Center for Molecular Medicine Cologne

Bazzi, Hisham - assoc. RG 02

The mechanisms monitoring cell division in stem cells

Abstract

The regulation of cell division is crucial for the propagation of multicellular organisms and aberrations in proliferation are at the origin of cancer. We and others have recently discovered a novel pathway that is mediated by 53BP1, USP28 and p53 and monitors the duration of mitosis in the mouse in vivo and in cell lines in vitro. This “mitotic surveillance pathway” is activated upon prolonging mitosis through centrosome loss of function or mitotic drugs, and is largely independent of the well-studied spindle assembly checkpoint (SAC), DNA damage or aneuploidy. We hypothesize that this pathway is a bone fidecheckpoint that operates as a “mitotic timer” that monitors cell division duration. Our aim is to dissect the mechanism of this novel cell cycle “checkpoint” from the sensors to the mediators using live-imaging, biochemical and genetic approaches in mouse embryonic stem cells (mESCs).

Figure 1

Clinical and Medical Relevance

How aberrations in cell division lead to human diseases such as microcephaly and malignancies like cancer are still open questions. Our work has defined a new p53-dependent pathway that monitors centrosomes and mitosis and ensures that only cells with normal mitotic duration are propagated. Our long-term goal of dissecting this mitotic surveillance pathway is to find druggable targets to help cure microcephaly during development and prevent cancer cells from proliferation and expansion.

  • Damen, M., Wirtz, L., Soroka, E., Khatif, H., Kukat, C., Simons, B.D., Bazzi, H#. (2021). High proliferation and delamination during skin epidermal stratification. Nat Commun 12(1), 3227.
  • Xiao, C.*, Grzonka, M.*, Meyer-Gerards, C, Mack, M., Figge, R., Bazzi, H#. (2021). Gradual centriole maturation associates with the mitotic surveillance pathway in mouse development. EMBO Rep 22(2), e51127. * Co-first authorship.
  • Phan, T., Maryniak, A.L., Boatwright, C.A., Lee, J., Atkins, A., Tijhuis, A., Spierings, D.C.J., Bazzi, H., Foijer, F., Jordan, P.W., Stracker, T.H., Holland, A.J. (2021). Centrosome defects cause microcephaly by activating the 53BP1-USP28-TP53 mitotic surveillance pathway. EMBO J 40(1), e106118.
  • Bazzi, H.#, Soroka, E., Alcorn, H., Anderson, K.V.#. (2017). STRIP1, a core component of STRIPAK complexes, is essential for normal mesoderm migration in the mouse embryo. Proc Natl Acad Sci U S A 114(51), E10928-E10936. # Co-correspondence.
  • Insolera, R.*, Bazzi, H.*, Shao, W., Shi, S.H., Anderson, K.V. (2014). Cortical neurogenesis in the absence of centrioles. Nat Neurosci 17(11), 1528-35. * Co-first authorship.
  • Bazzi, H., Anderson, K.V. (2014). Acentriolar mitosis activates a p53-dependent apoptosis pathway in the mouse embryo. Proc Natl Acad Sci U S A 111 (15), E1491-500.
  • Crispatzu G, Rehimi R, Pachano T, Bleckwehl T, Cruz-Molina S, Xiao C, Mahabir E, Bazzi H, and Rada-Iglesias A (2021). The chromatin, topological and regulatory properties of pluripotency-associated poised enhancers are conserved in vivo. Nat Commun12, 4344. doi:10.1038/s41467-021-24641-4.
  • Damen M, Wirtz L, Soroka E, Khatif H, Kukat C, Simons BD, and Bazzi H (2021). High proliferation and delamination during skin epidermal stratification. Nat Commun12, 3227. doi:10.1038/s41467-021-23386-4.
Dr. Hisham Bazzi CMMC Cologne
Dr. Hisham Bazzi

Clinic of Dermatology and Venereology

CMMC - PI - assoc. RG 02

+49 221 478 84385

Clinic of Dermatology and Venereology

Joseph-Stelzmann-Str. 26

50931 Cologne

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Curriculum Vitae (CV)

Publications on PubMed

Publications - Hishami Bazzi

Link to PubMed

Group Members

Houda Khatif
Marta Grzonka
Charlotte Meyer-Gerards
Lisa Wirtz