RAD52-dependent mitotic DNA synthesis is required for genome stability in Cyclin E1-overexpressing cells

Anastasia Audrey, Yannick P Kok, Shibo Yu, Lauren de Haan, Bert van de Kooij, Nathalie van den Tempel, Mengting Chen, H Rudolf de Boer, Bert van der Vegt, Marcel A T M van Vugt*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

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.

Original languageEnglish
Article number114116
Number of pages19
JournalCell reports
Volume43
Issue number4
DOIs
Publication statusPublished - 23-Apr-2024

Keywords

  • Humans
  • Cyclin E/metabolism
  • Genomic Instability
  • Rad52 DNA Repair and Recombination Protein/metabolism
  • Mitosis
  • Oncogene Proteins/metabolism
  • DNA Replication
  • Cell Line, Tumor
  • DNA Damage
  • DNA/metabolism
  • Breast Neoplasms/genetics

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