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The tumor suppressor Cdc73 functionally associates with CPSF and CstF 3' mRNA processing factors
Orit Rozenblatt-Rosen1, Takashi Nagaike, Joshua M Francis
1Department of Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA 02115, USA.
Summary
The Cdc73 protein links tumor suppression to mRNA processing. It helps attach essential factors for 3' mRNA maturation, impacting gene regulation and potentially preventing parathyroid tumors.
Area of Science:
- Molecular Biology
- Cancer Genetics
- RNA Processing
Background:
- The CDC73 tumor suppressor gene is frequently inactivated in parathyroid tumors.
- Cdc73 protein is a known component of the Paf1 complex, involved in RNA polymerase II regulation.
Purpose of the Study:
- To investigate the role of Cdc73 protein in mRNA processing.
- To identify direct targets and molecular mechanisms of Cdc73 function.
Main Methods:
- Immunodepletion assays to assess the necessity of the Cdc73 complex in 3' mRNA processing.
- Microarray analysis to identify Cdc73-regulated genes.
- siRNA-mediated depletion of Cdc73 to study its in vivo effects on gene expression and chromatin association.
Main Results:
- Cdc73 physically associates with cleavage and polyadenylation specificity factor (CPSF) and cleavage stimulation factor (CstF) complexes.
- The Cdc73-CPSF-CstF complex is essential for 3' mRNA processing in vitro.
- INTS6, encoding an Integrator complex subunit, was identified as a direct in vivo target of Cdc73.
- Cdc73 depletion reduced INTS6 mRNA levels and the association of CPSF/CstF with the INTS6 gene locus.
Conclusions:
- Cdc73 facilitates the recruitment of 3' mRNA processing factors to actively transcribed chromatin.
- These findings highlight a crucial link between tumor suppression (via CDC73) and the fundamental process of mRNA maturation.
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