The dimerization/repression domain of RFX1 is related to a conserved region of its yeast homologues crt1 and sak1: a new function for an ancient motif 1 1Edited by A. Klug

Katan-Khaykovich, Yael; Spiegel, Ivo; Shaul, Yosef

doi:10.1006/jmbi.1999.3245

Cited by 15 publications

(19 citation statements)

References 48 publications

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“…In humans the Rfx protein family consists of five members which function in various biological systems (6,10,12,14,38,39,42,43). On the basis of domain-swapping experiments we have concluded that Rfx1 is the homologue of Crt1 (25). Also, unlike the other mammalian Rfx homologues that function in specific tissues and/or developmental stages, Rfx1 is ubiquitously expressed, supporting the possibility that like Crt1, Rfx1 has a general and basic cellular function.…”

Section: Discussionmentioning

confidence: 74%

“…Altogether, these experiments indicate that Rfx1 is autorepressed. In this regard Rfx1 is surprisingly similar to the yeast homologue Crt1 not only on the level of structure (25) and target DNA sequence but also on the level of their transcription regulation.…”

Section: Discussionmentioning

confidence: 98%

“…The sequence and functional conservation between mammalian and yeast Rfx proteins is at the DNA-binding domain and the protein-protein interaction domain, as has been demonstrated by domain-swapping experiments (25). The level of conservation raises the possibility that the Rfx family has also retained its roles along the course of evolution.…”

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confidence: 88%

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Autorepression of Rfx1 Gene Expression: Functional Conservation from Yeast to Humans in Response to DNA Replication Arrest

Lubelsky

Reuven

Shaul

2005

Molecular and Cellular Biology

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The yeast Saccharomyces cerevisiae Crt1 transcription repressor is an effector of the DNA damage and replication checkpoint pathway. Crt1 binds and represses genes encoding ribonucleotide reductase (RNR) and its own promoter, establishing a negative-feedback pathway. The role of Rfx1, the mammalian Crt1 homologue, remained uncertain. In this study we investigated the possibility that Rfx1 plays a similar function in animal cells. We show here that, like Crt1, Rfx1 binds and represses its own promoter. Furthermore, Rfx1 binding to its promoter is reduced upon induction of a DNA replication block by hydroxyurea, which led to a release of repression. Significantly, like Crt1, Rfx1 binds and represses the RNR-R2 gene. Upon blocking replication and UV treatment, expression of both Rfx1 and RNR-R2 is induced; however, unlike the results seen with the RNR-R2 gene, the derepression of the RFX1 gene is only partially blocked by inhibiting Chk1, the DNA checkpoint kinase. This report provides evidence for a common mechanism for Crt1 and Rfx1 expression and for the conservation of their mode of action in response to a DNA replication block. We suggest that Rfx1 plays a role in the DNA damage response by down-regulating a subset of genes whose expression is increased in response to replication blocking and UV-induced DNA damage.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 98%

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Autorepression of Rfx1 Gene Expression: Functional Conservation from Yeast to Humans in Response to DNA Replication Arrest

Lubelsky

Reuven

Shaul

2005

Molecular and Cellular Biology

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“…In one line of homozygous mice, a morphologically identifiable dorsal midline was absent from the cerebral cortex. The mutation was mapped to the Rfx4 locus, and sequencing revealed a base substitution that changed a leucine residue to a proline within the conserved carboxyl-terminal domain of RFX4's larger dimerization domain (Katan-Khaykovich et al, 1999), suggesting that RFX4_v3-containing dimers regulate important transcriptional events during cortical midline formation. In the homozygous mouse brain, the defects caused by the missense mutation were very similar to the phenotype generated by insertional mutations in our laboratories, further supporting the importance of RFX4_v3 in the development of midline brain structures.…”

Section: Rfx4_v3 and Midline Brain Structure Formationmentioning

confidence: 99%

Regulatory factor X4 variant 3: A transcription factor involved in brain development and disease

Zhang

Zeldin

Blackshear

2007

J of Neuroscience Research

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Regulatory factor X4 variant 3 (RFX4_v3) is a recently identified transcription factor specifically expressed in the brain. Gene disruption in mice demonstrated that interruption of a single allele (heterozygous, +/−) prevented formation of the subcommissural organ (SCO), resulting in congenital hydrocephalus, whereas interruption of two alleles (homozygous, −/−) caused fatal failure of dorsal midline brain structure formation. These mutagenesis studies implicated RFX4_v3 in early brain development as well as the genesis of the SCO. Rfx4_v3 deficiency presumably causes abnormalities in brain by altering the expression levels of many genes that are crucial for brain morphogenesis, such as the signaling components in the Wnt, bone morphogenetic protein, and retinoic acid pathways. RFX4_v3 might affect these critical signaling pathways in brain development. Cx3cl1, a chemokine gene highly expressed in brain, was identified as a direct target for RFX4_v3, indicating that RFX4_v3 possesses trans-acting activity to stimulate gene expression. Rfx4_v3 is highly expressed in the suprachiasmatic nucleus and might be involved in regulating the circadian clock. One haplotype in RFX4_v3 gene is linked to a higher risk of bipolar disorder, suggesting that this protein might contribute to the pathogenesis of the disease. This Mini-Review describes our current knowledge about RFX4_v3, an important protein that appears to be involved in many aspects of brain development and disease. Keywords regulatory factor X; hydrocephalus; midline; brain development Regulatory factor X (RFX) members belong to the winged-helix subfamily of helix-turn-helix transcription factors, which share a highly conserved 76-amino-acid DNA binding domain (DBD) that is distinct from any other DBD (Gajiwala et al., 2000). These proteins regulate the expression of their target genes by binding to symmetrical "X-box" consensus sequences (Gajiwala et al., 2000). RFX family members have been identified in a broad range of

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“…Its homologues in higher eukaryotes are generally referred to as RFX proteins. In contrast to the human RFX proteins, which are known to be involved in both the activation and repression of transcription (21,22,36), Crt1 was initially isolated as a repressor and was shown to dissociate from the target promoter upon induction, arguing against a role in activation (20). However, Crt1 was later found to interact with TFIID, which generally acts as a coactivator (23), suggesting that it may have activator functions at DNA damage-inducible genes or other genes in vivo.…”

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confidence: 99%

Molecular Genetic Analysis of the Yeast Repressor Rfx1/Crt1 Reveals a Novel Two-Step Regulatory Mechanism

Zhang

Reese

2005

Molecular and Cellular Biology

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In Saccharomyces cerevisiae, the repressor Crt1 and the global corepressor Ssn6-Tup1 repress the DNA damage-inducible ribonucleotide reductase (RNR) genes. Initiation of DNA damage signals causes the release of Crt1 and Ssn6-Tup1 from the promoter, coactivator recruitment, and derepression of transcription, indicating that Crt1 plays a crucial role in the switch between gene repression and activation. Here we have mapped the functional domains of Crt1 and identified two independent repression domains and a region required for gene activation. The N terminus of Crt1 is the major repression domain, it directly binds to the Ssn6-Tup1 complex, and its repression activities are dependent upon Ssn6-Tup1 and histone deacetylases (HDACs). In addition, we identified a C-terminal repression domain, which is independent of Ssn6-Tup1 and HDACs and functions at native genes in vivo. Furthermore, we show that TFIID and SWI/SNF bind to a region within the N terminus of Crt1, overlapping with but distinct from the Ssn6-Tup1 binding and repression domain, suggesting that Crt1 may have activator functions. Crt1 mutants were constructed to dissect its activator and repressor functions. All of the mutants were competent for repression of the DNA damage-inducible genes, but a majority were "derepression-defective" mutants. Further characterization of these mutants indicated that they are capable of receiving DNA damage signals and releasing the Ssn6-Tup1 complex from the promoter but are selectively impaired for TFIID and SWI/SNF recruitment. These results imply a two-step activation model of the DNA damage-inducible genes and that Crt1 functions as a signal-dependent dual-transcription activator and repressor that acts in a transient manner.

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The dimerization/repression domain of RFX1 is related to a conserved region of its yeast homologues crt1 and sak1: a new function for an ancient motif 1 1Edited by A. Klug

Cited by 15 publications

References 48 publications

Autorepression of Rfx1 Gene Expression: Functional Conservation from Yeast to Humans in Response to DNA Replication Arrest

Autorepression of Rfx1 Gene Expression: Functional Conservation from Yeast to Humans in Response to DNA Replication Arrest

Regulatory factor X4 variant 3: A transcription factor involved in brain development and disease

Molecular Genetic Analysis of the Yeast Repressor Rfx1/Crt1 Reveals a Novel Two-Step Regulatory Mechanism

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