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Published on: March 21, 2018
CtIP, a candidate tumor susceptibility gene is a team player with luminaries
1Institute for Molecular Virology, Saint Louis University School of Medicine, 3681 Park Avenue, St. Louis, Missouri 63110, USA. chinnag@slu.edu
Abstract:
CtIP is a nuclear protein conserved among vertebrates that was discovered as a cofactor of the transcriptional corepressor CtBP. CtIP also interacts with the tumor suppressors such as BRCA1 and the pRb family members through binding sites that are frequently mutated in human cancers. CtIP is a target for BRCA1-dependent phosphorylation by the ATM kinase induced by DNA double strand breakage. CtIP plays a role in DNA-damage-induced cell cycle checkpoint control at the G2/M transition. Homozygous inactivation of the Ctip gene causes very early embryonic lethality during mouse development. The Ctip(-/-) embryo cells are arrested in G1 and do not enter S phase. Depletion of Ctip in established mouse embryo fibroblasts arrests cells in G1 and results in an accumulation of hypophosphorylated Rb and the Cdk inhibitor p21, suggesting that CtIP is also a critical regulator of G1/S transition of the cell cycle. The Ctip gene contains a mononucleotide (A9) repeat and one of the alleles is mutated at a high frequency in colon cancers with microsatellite instability. The Ctip(+/-) mice develop multiple types of tumors suggesting that haploid insufficiency of Ctip leads to tumorigenesis. Among the various tumor types observed in Ctip(+/-) heterozygous mice, large lymphomas are prevalent. Recent studies raise the possibility that Ctip may itself be a tumor susceptibility gene and suggest that it might be important for the activities of tumor suppressors BRCA1, pRb family proteins and Ikaros family members.
Insights
CtIP protein is crucial for cell cycle regulation and DNA repair. Its inactivation leads to embryonic lethality and tumor development, highlighting its role as a tumor suppressor.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- CtIP (CtBP-interacting protein) is a nuclear protein interacting with transcriptional corepressor CtBP.
- CtIP binds to tumor suppressors BRCA1 and pRb family proteins, with mutations in these sites linked to human cancers.
- CtIP is phosphorylated by ATM kinase upon DNA double-strand breaks, mediating DNA damage responses.
Purpose of the Study:
- To investigate the role of CtIP in cell cycle control and DNA damage response.
- To determine the consequences of CtIP gene inactivation or haploid insufficiency in mammalian development and tumorigenesis.
Main Methods:
- Studied CtIP's interactions with BRCA1, pRb family members, and CtBP.
- Investigated CtIP's role in DNA-damage-induced cell cycle checkpoints using ATM kinase.
- Analyzed the effects of homozygous and heterozygous Ctip gene inactivation in mouse models and embryo fibroblasts.
Main Results:
- Homozygous Ctip inactivation caused embryonic lethality with G1 cell cycle arrest.
- CtIP depletion in fibroblasts led to G1 arrest, hypophosphorylated Rb, and p21 accumulation, indicating G1/S transition regulation.
- Ctip haploid insufficiency in mice resulted in multiple tumor types, particularly lymphomas, suggesting CtIP is a tumor susceptibility gene.
Conclusions:
- CtIP is essential for embryonic development and cell cycle progression at the G1/S and G2/M transitions.
- CtIP functions as a tumor suppressor, and its haploid insufficiency promotes tumorigenesis.
- CtIP is critical for the activity of tumor suppressors like BRCA1 and pRb family proteins.
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