| Structural highlights
Function
[PUF60_HUMAN] DNA- and RNA-binding protein, involved in several nuclear processes such as pre-mRNA splicing, apoptosis and transcription regulation. In association with FUBP1 regulates MYC transcription at the P2 promoter through the core-TFIIH basal transcription factor. Acts as a transcriptional repressor through the core-TFIIH basal transcription factor. Represses FUBP1-induced transcriptional activation but not basal transcription. Decreases ERCC3 helicase activity. Does not repress TFIIH-mediated transcription in xeroderma pigmentosum complementation group B (XPB) cells. Is also involved in pre-mRNA splicing. Promotes splicing of an intron with weak 3'-splice site and pyrimidine tract in a cooperative manner with U2AF2. Involved in apoptosis induction when overexpressed in HeLa cells. Isoform 6 failed to repress MYC transcription and inhibited FIR-induced apoptosis in colorectal cancer. Isoform 6 may contribute to tumor progression by enabling increased MYC expression and greater resistance to apoptosis in tumors than in normal cells. Modulates alternative splicing of several mRNAs. Binds to relaxed DNA of active promoter regions. Binds to the pyrimidine tract and 3'-splice site regions of pre-mRNA; binding is enhanced in presence of U2AF2. Binds to Y5 RNA in association with TROVE2. Binds to poly(U) RNA.[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
c-myc is essential for cell homeostasis and growth but lethal if improperly regulated. Transcription of this oncogene is governed by the counterbalancing forces of two proteins on TFIIH--the FUSE binding protein (FBP) and the FBP-interacting repressor (FIR). FBP and FIR recognize single-stranded DNA upstream of the P1 promoter, known as FUSE, and influence transcription by oppositely regulating TFIIH at the promoter site. Size exclusion chromatography coupled with light scattering reveals that an FIR dimer binds one molecule of single-stranded DNA. The crystal structure confirms that FIR binds FUSE as a dimer, and only the N-terminal RRM domain participates in nucleic acid recognition. Site-directed mutations of conserved residues in the first RRM domain reduce FIR's affinity for FUSE, while analogous mutations in the second RRM domain either destabilize the protein or have no effect on DNA binding. Oppositely oriented DNA on parallel binding sites of the FIR dimer results in spooling of a single strand of bound DNA, and suggests a mechanism for c-myc transcriptional control.
Dimerization of FIR upon FUSE DNA binding suggests a mechanism of c-myc inhibition.,Crichlow GV, Zhou H, Hsiao HH, Frederick KB, Debrosse M, Yang Y, Folta-Stogniew EJ, Chung HJ, Fan C, De la Cruz EM, Levens D, Lolis E, Braddock D EMBO J. 2008 Jan 9;27(1):277-89. Epub 2007 Dec 6. PMID:18059478[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Liu J, He L, Collins I, Ge H, Libutti D, Li J, Egly JM, Levens D. The FBP interacting repressor targets TFIIH to inhibit activated transcription. Mol Cell. 2000 Feb;5(2):331-41. PMID:10882074
- ↑ Page-McCaw PS, Amonlirdviman K, Sharp PA. PUF60: a novel U2AF65-related splicing activity. RNA. 1999 Dec;5(12):1548-60. PMID:10606266
- ↑ Liu J, Akoulitchev S, Weber A, Ge H, Chuikov S, Libutti D, Wang XW, Conaway JW, Harris CC, Conaway RC, Reinberg D, Levens D. Defective interplay of activators and repressors with TFIH in xeroderma pigmentosum. Cell. 2001 Feb 9;104(3):353-63. PMID:11239393
- ↑ Matsushita K, Tomonaga T, Shimada H, Shioya A, Higashi M, Matsubara H, Harigaya K, Nomura F, Libutti D, Levens D, Ochiai T. An essential role of alternative splicing of c-myc suppressor FUSE-binding protein-interacting repressor in carcinogenesis. Cancer Res. 2006 Feb 1;66(3):1409-17. PMID:16452196 doi:http://dx.doi.org/10.1158/0008-5472.CAN-04-4459
- ↑ Liu J, Kouzine F, Nie Z, Chung HJ, Elisha-Feil Z, Weber A, Zhao K, Levens D. The FUSE/FBP/FIR/TFIIH system is a molecular machine programming a pulse of c-myc expression. EMBO J. 2006 May 17;25(10):2119-30. Epub 2006 Apr 20. PMID:16628215 doi:http://dx.doi.org/7601101
- ↑ Hastings ML, Allemand E, Duelli DM, Myers MP, Krainer AR. Control of pre-mRNA splicing by the general splicing factors PUF60 and U2AF65. PLoS One. 2007 Jun 20;2(6):e538. PMID:17579712 doi:http://dx.doi.org/10.1371/journal.pone.0000538
- ↑ Crichlow GV, Zhou H, Hsiao HH, Frederick KB, Debrosse M, Yang Y, Folta-Stogniew EJ, Chung HJ, Fan C, De la Cruz EM, Levens D, Lolis E, Braddock D. Dimerization of FIR upon FUSE DNA binding suggests a mechanism of c-myc inhibition. EMBO J. 2008 Jan 9;27(1):277-89. Epub 2007 Dec 6. PMID:18059478
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