| Autor: |
Audrey, Anastasia, Kok, Yannick P., Yu, Shibo, de Haan, Lauren, van de Kooij, Bert, van den Tempel, Nathalie, Chen, Mengting, de Boer, H. Rudolf, van der Vegt, Bert, van Vugt, Marcel A.T.M. |
| Zdroj: |
Cell Reports; Apr2024, Vol. 43 Issue 4, pN.PAG-N.PAG, 1p |
| Abstrakt: |
Overexpression of Cyclin E1 perturbs DNA replication, resulting in DNA lesions and genomic instability. Consequently, Cyclin E1-overexpressing cancer cells increasingly rely on DNA repair, including RAD52-mediated break-induced replication during interphase. We show that not all DNA lesions induced by Cyclin E1 overexpression are resolved during interphase. While DNA lesions upon Cyclin E1 overexpression are induced in S phase, a significant fraction of these lesions is transmitted into mitosis. Cyclin E1 overexpression triggers mitotic DNA synthesis (MiDAS) in a RAD52-dependent fashion. Chemical or genetic inactivation of MiDAS enhances mitotic aberrations and persistent DNA damage. Mitosis-specific degradation of RAD52 prevents Cyclin E1-induced MiDAS and reduces the viability of Cyclin E1-overexpressing cells, underscoring the relevance of RAD52 during mitosis to maintain genomic integrity. Finally, analysis of breast cancer samples reveals a positive correlation between Cyclin E1 amplification and RAD52 expression. These findings demonstrate the importance of suppressing mitotic defects in Cyclin E1-overexpressing cells through RAD52. [Display omitted] • Cyclin E1 overexpression induces S-phase DNA lesions, which are carried into mitosis • Cyclin E1 overexpression leads to RAD52-dependent mitotic DNA synthesis • R-loop formation and nucleotide pool depletion contribute to mitotic DNA synthesis • RAD52 inactivation in these cells causes inherited DNA damage and reduced viability Overexpression of the proto-oncogene Cyclin E1 leads to perturbed replication. Audrey et al. discover that Cyclin E1 overexpression causes transmission of DNA lesions into mitosis, which triggers RAD52-dependent mitotic DNA synthesis. Inactivation of RAD52 in these cells gives rise to an accumulation of DNA lesions in daughter cells and decreased viability. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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