Cleavage stimulation factor

Cleavage stimulatory factor or cleavage stimulation factor (CstF or CStF) is a heterotrimeric protein involved in the cleavage of the 3' signaling region from a newly synthesized pre-messenger RNA (mRNA) molecule.^[1] It recognizes U/GU‑rich elements (GREs) downstream of pre‑mRNA cleavage sites and promotes endonucleolytic cleavage and subsequent polyadenylation (poly(A)) of eukaryotic pre‑mRNAs.^[2]

CstF is recruited by cleavage and polyadenylation specificity factor (CPSF) and assembles into a protein complex on the 3' end to promote the synthesis of a functional polyadenine tail (poly(A) tail), which results in a mature mRNA molecule ready to be exported from the cell nucleus to the cytosol for translation.^[2]

CstF is made up of the proteins CSTF1, CSTF2 and CSTF3, totaling about 200 kDa.^[3] CSTF2 is the primary RNA-binding subunit that recognizes GREs downstream of the cleavage site.^[2]

The amount of CstF in a cell is dependent on the phase of the cell cycle, increasing significantly during the transition from G0 phase to S phase in mouse fibroblast and human splenic B cells.^[4]

Structure

CstF is made of three subunits that each perform different functions of the larger protein complex.^[1] The subunits interact with each other to stabilize the complex and increase poly(A) efficiency.^[3]

CSTF1 (also referred to as CstF-50) is the smallest subunit of CstF weighing around 50 kDa.^[3] It interacts with CSTF3 to support complex assembly, though the full mechanism is unknown.^[5] 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.^[6] Additionally, its N-terminus mediates homodimerization.^[7]

The second-largest CstF subunit is CSTF2 (also referred to as CstF-64) weighing around 64 kDa.^[3] It is the primary RNA-binding subunit and contains an RNA recognition motif (RRM) that binds to GREs in pre-mRNA.^[8] 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.^[9]

CSTF3 (also referred to as CstF-77) is the largest subunit of CstF weighing around 77 kDa.^[3] It holds the larger complex together and stabilizes interactions between CSTF2 and 3'-end factors such as symplekin.^[10] It also interacts with CPSF subunit CPSF160, which is partially responsible for poly(A) site specification and synthesis of the poly(A) tail.^[11]

Clinical significance

Cancer

Some studies have identified CSTF2 as a potential target for cancer detection and progression.^[12][13] 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.^[12] CSTF2 has been suggested for use as a biomarker for early cancer diagnosis and potential target for future drugs.^[13] There are currently no clinical applications of CSTF2 or CstF.^[13]