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Overexpression of Cyclin E1 or Cdc25A leads to replication stress, mitotic aberrancies, and increased sensitivity to replication checkpoint inhibitors
- Source :
- Oncogenesis, Vol 9, Iss 10, Pp 1-15 (2020), Oncogenesis, 9(10):88. Nature Publishing Group, Oncogenesis
- Publication Year :
- 2020
- Publisher :
- Nature Publishing Group, 2020.
-
Abstract
- Oncogene-induced replication stress, for instance as a result of Cyclin E1 overexpression, causes genomic instability and has been linked to tumorigenesis. To survive high levels of replication stress, tumors depend on pathways to deal with these DNA lesions, which represent a therapeutically actionable vulnerability. We aimed to uncover the consequences of Cyclin E1 or Cdc25A overexpression on replication kinetics, mitotic progression, and the sensitivity to inhibitors of the WEE1 and ATR replication checkpoint kinases. We modeled oncogene-induced replication stress using inducible expression of Cyclin E1 or Cdc25A in non-transformed RPE-1 cells, either in a TP53 wild-type or TP53-mutant background. DNA fiber analysis showed Cyclin E1 or Cdc25A overexpression to slow replication speed. The resulting replication-derived DNA lesions were transmitted into mitosis causing chromosome segregation defects. Single cell sequencing revealed that replication stress and mitotic defects upon Cyclin E1 or Cdc25A overexpression resulted in genomic instability. ATR or WEE1 inhibition exacerbated the mitotic aberrancies induced by Cyclin E1 or Cdc25A overexpression, and caused cytotoxicity. Both these phenotypes were exacerbated upon p53 inactivation. Conversely, downregulation of Cyclin E1 rescued both replication kinetics, as well as sensitivity to ATR and WEE1 inhibitors. Taken together, Cyclin E1 or Cdc25A-induced replication stress leads to mitotic segregation defects and genomic instability. These mitotic defects are exacerbated by inhibition of ATR or WEE1 and therefore point to mitotic catastrophe as an underlying mechanism. Importantly, our data suggest that Cyclin E1 overexpression can be used to select patients for treatment with replication checkpoint inhibitors.
- Subjects :
- CDK2
EXPRESSION
0301 basic medicine
Genome instability
Cancer Research
CDC25A
Mitosis
MYC
DNA replication
medicine.disease_cause
lcsh:RC254-282
Article
03 medical and health sciences
0302 clinical medicine
medicine
PHOSPHORYLATION
Molecular Biology
Mitotic catastrophe
WEE1 INHIBITOR
biology
Cyclin-dependent kinase 2
AMPLIFICATION
Oncogenes
CCNE1
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
3. Good health
Cell biology
Cyclin E1
Wee1
030104 developmental biology
030220 oncology & carcinogenesis
biology.protein
E DEREGULATION
PHOSPHATASES
Carcinogenesis
GENOMIC INSTABILITY
Subjects
Details
- Language :
- English
- ISSN :
- 21579024
- Volume :
- 9
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Oncogenesis
- Accession number :
- edsair.doi.dedup.....64a3cca2f6a1dedeee0c223671bd90ed