TBRG1, also known as NIAM (nuclear interactor of ARF and Mdm2), is a p53 activator that causes a G1 phase cell cycle arrest, and collaborates with ARF in an additive fashion to suppress proliferation []. NIAM has also been shown to associate with chromatin-associated protein and bind to Tip60 [].
The "FY-rich"domain N-terminal (FYRN) and "FY-rich"domain C-terminal (FYRC) sequence motifs are two poorly characterised phenylalanine/tyrosine-rich regions of around 50 and 100 amino acids, respectively, that arefound in a variety of chromatin-associated proteins [, , , ]. They areparticularly common in histone H3K4 methyltransferases most notably in afamily of proteins that includes human mixed lineage leukemia (MLL) and theDrosophila melanogaster protein trithorax. Both of these enzymes play a keyrole in the epigenetic regulation of gene expression during development, andthe gene coding for MLL is frequently rearranged in infant and secondarytherapy-related acute leukemias. They are also found in transforming growthfactor beta regulator 1 (TBRG1), a growth inhibitory protein induced in cellsundergoing arrest in response to DNA damage and transforming growth factor(TGF)-beta1. As TBRG1 has been shown to bind to both the tumor suppressorp14ARF and MDM2, a key regulator of p53, it is also known as nuclearinteractor of ARF and MDM2 (NIAM). In most proteins, the FYRN and FYRC regionsare closely juxtaposed, however, in MLL and its homologues they are fardistant. To be fully active, MLL must be proteolytically processed bytaspase1, which cleaves the protein between the FYRN and FYRC regions []. TheN-terminal and C-terminal fragments remain associated after proteolysisapparently as a result of an interaction between the FYRN and FYRC regions.How proteolytic processing regulates the activity of MLL is not known.Intriguingly, the FYRN and FYRC motifs of a second family of histone H3K4methyltransferases, represented by MLL2 and MLL4 in humans and TRR inDrosophila melanogaster, are closely juxtaposed. FYRN and FYRC motifs arefound in association with modules that create or recognise histonemodifications in proteins from a wide range of eukaryotes, and it is likelythat in these proteins they have a conserved role related to some aspect ofchromatin biology [].The FYRN and FYRC regions are not separate independently folded domains, butare components of a distinct protein module, The FYRN and FYRC motifs bothform part of a single folded module (the FYR domain), which adopts an alpha+beta fold consisting of a six-stranded antiparallel β-sheet followed byfour consecutive α-helices. The FYRN region correspondsto β-strands 1-4 and their connecting loops, whereas the FYRC motif maps toβ-strand 5, β-strand 6 and helices alpha1 to alpha4. Most of theconserved tyrosine and phenylalanine residues, after which these motifs arenamed are involved in interactions that stabilise the fold. Proteins such asMLL, in which the FYRN and FYRC regions are separated by hundreds of aminoacids, are expected to contain FYR domains with a large insertion between twoof the strands of the β-sheet (strands 4 and 5) [].
The "FY-rich"domain N-terminal (FYRN) and "FY-rich"domain C-terminal (FYRC) sequence motifs are two poorly characterised phenylalanine/tyrosine-rich regions of around 50 and 100 amino acids, respectively, that arefound in a variety of chromatin-associated proteins [, , , ]. They areparticularly common in histone H3K4 methyltransferases most notably in afamily of proteins that includes human mixed lineage leukemia (MLL) and theDrosophila melanogaster protein trithorax. Both of these enzymes play a keyrole in the epigenetic regulation of gene expression during development, andthe gene coding for MLL is frequently rearranged in infant and secondarytherapy-related acute leukemias. They are also found in transforming growthfactor beta regulator 1 (TBRG1), a growth inhibitory protein induced in cellsundergoing arrest in response to DNA damage and transforming growth factor(TGF)-beta1. As TBRG1 has been shown to bind to both the tumor suppressorp14ARF and MDM2, a key regulator of p53, it is also known as nuclearinteractor of ARF and MDM2 (NIAM). In most proteins, the FYRN and FYRC regionsare closely juxtaposed, however, in MLL and its homologues they are fardistant. To be fully active, MLL must be proteolytically processed bytaspase1, which cleaves the protein between the FYRN and FYRC regions []. TheN-terminal and C-terminal fragments remain associated after proteolysisapparently as a result of an interaction between the FYRN and FYRC regions.How proteolytic processing regulates the activity of MLL is not known.Intriguingly, the FYRN and FYRC motifs of a second family of histone H3K4methyltransferases, represented by MLL2 and MLL4 in humans and TRR inDrosophila melanogaster, are closely juxtaposed. FYRN and FYRC motifs arefound in association with modules that create or recognise histonemodifications in proteins from a wide range of eukaryotes, and it is likelythat in these proteins they have a conserved role related to some aspect ofchromatin biology [].The FYRN and FYRC regions are not separate independently folded domains, butare components of a distinct protein module, The FYRN and FYRC motifs bothform part of a single folded module (the FYR domain), which adopts an alpha+beta fold consisting of a six-stranded antiparallel β-sheet followed byfour consecutive α-helices. The FYRN region correspondsto β-strands 1-4 and their connecting loops, whereas the FYRC motif maps toβ-strand 5, β-strand 6 and helices alpha1 to alpha4. Most of theconserved tyrosine and phenylalanine residues, after which these motifs arenamed are involved in interactions that stabilise the fold. Proteins such asMLL, in which the FYRN and FYRC regions are separated by hundreds of aminoacids, are expected to contain FYR domains with a large insertion between twoof the strands of the β-sheet (strands 4 and 5) [].
