Tuftelin interacting protein 11 (TFIP11) was identified as a key human spliceosome assembly regulator that interacts with multiple spliceosomal proteins and localizes to several membraneless organelles. TFIP11 has been implicated in the regulation of RNA splicing and processing of pre-mRNA transcripts, suggesting a potential role in regulating mRNA maturation. TFIP11 is localized in a novel subnuclear compartment, termed the TFIP body, close to the SC35 domain.
TFIP11 prefers to bind to DNA substrates that are models of structures at deadlock replication forks. When one loses either TFIP11 or BLM, the other protein accumulates at dead end replication forks. This abnormal accumulation also corrupts RAD51-induced replication fork reverse and acceleration, primes cells for replicational stressors, and increases chromosomal instability. The data expose a novel regulator that turns on or off the activities of BLM and RAD51 at stopped forks, and therefore interferes with genome integrity.
Several experiments indicated that TFIP11 could also interact with other proteins to generate a complex needed for normal cell function, and that TFIP11 could be mis-expressed or mutational resulting in disease or developmental defects. But exactly what TFIP11 is actually doing in a disease process or exactly what it does biologically remains under active research.
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Functions of TFIP11
TFIP11 is a protein involved in many biological functions, including cell signalling and gene regulation. Chimps, rhesus monkeys, dogs, cows, mice, rats, chickens, zebrafish, fruit flies, caenorhabditis elegans, fission yeast, rice blast fungus, arabidopsis, rice and frogs all carry the TFIP11 gene. Today, there are 243 species with orthologs of the human gene TFIP11. TFIP11 is a key player in genome stability. Genome stability is how well cells replicate and pass genetic information from one generation to the next without mutations, chromosome switches and other genetic instabilities during cell division and growth. TFIP11 might do:
Regulating Transcription
TFIP11 might control expression of DNA repair, cell cycle control and chromosome stability genes through interactions with other transcription factors.
Participating in DNA Repair
TFIP11 could be involved in the DNA damage response to drive repair processes to engage and thus reduce DNA mutations and damage accumulation.
Maintaining Chromosome Structure
TFIP11 might also be required for chromosome normalization and function (to ward off chromosome translocation or breakage).
Responding to Cellular Stress
If cells are exposed to oxidative or other forms of environmental stress, TFIP11 could be activated to accommodate those changes and conserve the genome.
Fig. 1 TFIP11 co-localizes with mDEAH9 in vivo, and the two interact with each other and may play a role in late RNA splicing events(Wen, X.; et al. 2008).
Significance of Maintaining Genome Integrity
We need accurate and 100% copying of the genome to preserve it. But DNA replication is constantly stressed by both endogenous and exogenous factors, and this can result in replication forks stalling and genome instability. Cells that have their genome damaged can develop cancer and other genetic illnesses. Cells have to pass on the whole genome to the daughters cells correctly during division. Having a genome intact also helps organisms adapt to changes in the environment. Genome stability, for instance, makes cells repair and function normally when exposed to external forces (radiation, chemicals, etc). Good gene expression at all developmental levels depends on genome stability, and if damaged, it could produce developmental defects or growth disruption. By participating in splicing processes, TFIP11 keeps RNA processing up to date, and transmission of genes on the correct track. TFIP11 dysfunction can cause splice error, which in turn can cause genome instability and pathology.
Biological Functions of TFIP11
It is not just TFIP11's splicing function that is biologically relevant. TFIP11 is found in a special subnuclear structure called the TFIP body in the nucleus, which holds splicing elements. It is not only the fact that TFIP11 has multiple functions, but also its ability to keep things in the right state for splicing to work. In-house TFIP11 was easily co-immunoprecipitated with BLM antibody. Significantly, treatment with the ribonucleotide reductase inhibitor hydroxyurea (HU) mediated TFIP11's interaction with the BLM protein complex. This TFIP11-BLM interaction didn't react to benzonase, which precludes nucleic acid-bridging binding. These data, combined, show that TFIP11 binds to the BLM complex.
TFIP11 Keeps Genes Intact by Triggering Replication Fork Reversal
Replication fork reversal is a common reaction to replication stress in higher eukaryotic cells that proceeds through a chain of enzymatic steps. TFIP11 can keep stopped replication forks from going down by forcing replication fork reversal. When the replication fork is reversed, annealing the extruded initial DNA strand forms ssDNA ends on the degenerating arm that can be identified using native 5-bromo-2'-deoxyuridine (BrdU) immunofluorescence assay56. Replication fork reversal during replication stress basically prevents replication forks from running. Since replication fork reversal depends on TFIP11, knockdown of TFIP11 prevents replication stress-induced replication fork slowed progress. Its DNA binding activity is why TFIP11 promotes reversal and slowdown of stagnant forks during replication stress.
GCFC domain protein called TFIP11 was discovered by yeast two-hybrid screening as a tuftelin binding partner. TFIP11 might be involved in the cell's response to replication stress but it has not been investigated. TFIP11 controls BLM and RAD51 activity on stuck forks in replication fork reversal.
Conclusion
TFIP11 is an evolutionarily conserved GCFC domain-containing protein that plays an important role in RNA processing, from splicing regulation to replication fork reversal. TFIP11 interacts with a variety of biological molecules, which may induce conformational changes in the protein, thereby antagonizing each other to promote replication fork reversal and promote the complete expression of biological genes. However, the exact biological significance of this interaction is still unclear, and researchers are committed to exploring its biological role to reveal the mechanism of maintaining gene integrity.
References
- Tannukit, S.; et al. TFIP11, CCNL1 and EWSR1 protein-protein interactions, and their nuclear localization. International journal of molecular sciences 2008, 9(8): 1504-1514.
- Wen, X.; et al. TFIP11 interacts with mDEAH9, an RNA helicase involved in spliceosome disassembly. International Journal of Molecular Sciences 2008, 9(11): 2105-2113.
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