Cleavage stimulation factor

Structure

CstF is made of three subunits that each perform different functions of the larger protein complex. The subunits interact with each other to stabilize the complex and increase poly(A) efficiency.

CSTF1 (also referred to as CstF-50) is the smallest subunit of CstF weighing around 50 kDa. It interacts with CSTF3 to support complex assembly, though the full mechanism is unknown. Studies speculate that CSTF1 acts as a clamp at the CSTF2 binding site on CSTF3, reducing flexibility in the bond and creating more favorable RNA binding. Additionally, its N-terminus mediates homodimerization.

The second-largest CstF subunit is CSTF2 (also referred to as CstF-64) weighing around 64 kDa. It is the primary RNA-binding subunit and contains an RNA recognition motif (RRM) that binds to GREs in pre-mRNA. This binding attaches the poly(A) tail to the 3' end of pre-mRNAs, resulting in mature RNA. CSTF2 also affects cell growth, with studies finding that a significant reduction of CSTF2 in B cells reduces m-RNA accumulation and causes apoptosis upon depletion.

CSTF3 (also referred to as CstF-77) is the largest subunit of CstF weighing around 77 kDa. It holds the larger complex together and stabilizes interactions between CSTF2 and 3'-end factors such as symplekin. It also interacts with CPSF subunit CPSF160, which is partially responsible for poly(A) site specification and synthesis of the poly(A) tail.

Clinical significance

Cancer

Some studies have identified CSTF2 as a potential target for cancer detection and progression. Certain cancers, including prostate cancer, breast cancer and pancreatic cancer, have been associated with elevated CSTF2 expression, suggesting that it contributes to the pathological development and progression of cancer. CSTF2 has been suggested for use as a biomarker for early cancer diagnosis and potential target for future drugs. There are currently no clinical applications of CSTF2 or CstF.

References

References

1. (2021-01-01). "MRNA 3' End Processing and Metabolism". Academic Press.
2. (1997-10-17). "RNA Ligands Selected by Cleavage Stimulation Factor Contain Distinct Sequence Motifs That Function as Downstream Elements in 3′-End Processing of Pre-mRNA *". Journal of Biological Chemistry.
3. (2000-03-01). "Complex protein interactions within the human polyadenylation machinery identify a novel component.". Molecular and Cellular Biology.
4. (1998). "Increase in the 64-kDa subunit of the polyadenylation/cleavage stimulatory factor during the G0 to S phase transition". Proceedings of the National Academy of Sciences of the United States of America.
5. Bank, RCSB Protein Data. "RCSB PDB - 6B3X: Crystal structure of CstF-50 in complex with CstF-77".
6. (2018-01-25). "Reconstitution of the CstF complex unveils a regulatory role for CstF-50 in recognition of 3′-end processing signals". Nucleic Acids Research.
7. (2011-03-01). "Hexameric architecture of CstF supported by CstF-50 homodimerization domain structure". RNA.
8. Masoumzadeh, Elahe. (May 2021). "Structure and dynamics of CstF-64 RNA recognition motif drive cleavage and polyadenylation".
9. (1998-12-01). "Levels of Polyadenylation Factor CstF-64 Control IgM Heavy Chain mRNA Accumulation and Other Events Associated with B Cell Differentiation". Molecular Cell.
10. (2011-01-01). "Interactions of CstF-64, CstF-77, and symplekin: implications on localisation and function". Molecular Biology of the Cell.
11. (1995-11-01). "The 160-kD subunit of human cleavage-polyadenylation specificity factor coordinates pre-mRNA 3'-end formation". Genes & Development.
12. (2023-12-17). "The role of CSTF2 in cancer: from technology to clinical application". Cell Cycle.
13. (2022-03-18). "Cleavage Stimulation Factor Subunit 2: Function Across Cancers and Potential Target for Chemotherapeutic Drugs". Frontiers in Pharmacology.