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Disruption of Trrap causes early embryonic lethality and defects in cell cycle progression
1International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, F-69008, Lyon, France.
Abstract:
The transactivation/transformation-domain associated protein (TRRAP) belongs to the Ataxia-telangiectasia mutated (ATM) super-family and has been identified as a cofactor for c-MYC-mediated oncogenic transformation. TRRAP and its yeast homolog (Tra1p) are components of histone acetyltransferase (HAT) complexes, SAGA (refs. 2,4,5), PCAF (ref. 3) and NuA4 (ref. 6), which are important for the regulation of transcription and cell cycle progression and also have a role in cell viability. Yet the biological function of this molecule and how it controls proliferation are still unclear. Here we show that null mutation of Trrap in mice results in peri-implantation lethality due to a blocked proliferation of blastocysts. We use an inducible Cre-loxP system to show that loss of Trrap blocks cell proliferation because of aberrant mitotic exit accompanied by cytokinesis failure and endoreduplication. Trrap-deficient cells fail to sustain mitotic arrest despite chromosome missegregation and disrupted spindles, and display compromised cdk1 activity. Trrap is therefore essential for early development and required for the mitotic checkpoint and normal cell cycle progression.
Insights
The transactivation/transformation-domain associated protein (TRRAP) is essential for early mouse development. Loss of TRRAP blocks blastocyst proliferation by disrupting cell cycle progression and mitotic exit, leading to developmental lethality.
Area of Science:
- Molecular Biology
- Developmental Biology
- Genetics
Background:
- The transactivation/transformation-domain associated protein (TRRAP) is part of histone acetyltransferase complexes involved in transcription and cell cycle regulation.
- TRRAP's precise biological function and control over cell proliferation remain unclear.
- TRRAP belongs to the Ataxia-telangiectasia mutated (ATM) super-family and acts as a cofactor in c-MYC-mediated oncogenic transformation.
Purpose of the Study:
- To elucidate the biological function of TRRAP in early development.
- To investigate the role of TRRAP in cell proliferation and cell cycle progression.
Main Methods:
- Generation of Trrap null mutant mice.
- Utilized an inducible Cre-loxP system for conditional gene knockout.
- Analyzed blastocyst proliferation, cell cycle progression, and mitotic events in Trrap-deficient cells.
Main Results:
- Trrap null mutation in mice causes peri-implantation lethality due to blocked blastocyst proliferation.
- Loss of Trrap leads to aberrant mitotic exit, cytokinesis failure, and endoreduplication.
- Trrap-deficient cells exhibit compromised cdk1 activity and fail to sustain mitotic arrest despite chromosome missegregation and spindle disruption.
Conclusions:
- TRRAP is essential for early embryonic development in mice.
- TRRAP plays a critical role in maintaining the mitotic checkpoint and ensuring normal cell cycle progression.
- TRRAP is required for proper mitotic exit and cytokinesis, preventing errors like endoreduplication.