Homeodomain-DNA Recognition

Gehring, Walter J.; Yan, Qiu Qian; Billeter, Martin; Furukubo-Tokunaga, Katsuo; Schier, Alexander F.; Reséndez‐Pérez, Diana; Affolter, Markus; Otting, Gottfried; Wüthrich, Kurt

doi:10.1142/9789812795830_0042

Cited by 109 publications

(166 citation statements)

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“…In order to determine whether DNA binding is required, we generated mutations in critical homeodomain amino acids in our protein expression constructs. Previous work has shown that amino acids 51 and 53 of the homeodomain are essential for DNA binding of homeobox proteins (Gehring et al, 1994; Laughon, 1991), so mutation of these sites were generated for both Hoxa2 and Hoxa11 (Figure 4). The ability of Hoxa2 to repress, and of Hoxa11 to activate, Six2 expression is significantly reduced when the DNA binding domain of either protein is mutated, demonstrating that DNA binding is a critical component of both Hox activation and repression (Figure 7).…”

Section: Resultsmentioning

confidence: 99%

Non-homeodomain regions of Hox proteins mediate activation versus repression of Six2 via a single enhancer site in vivo

Yallowitz

Gong

Swinehart

et al. 2009

Developmental Biology

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Summary Hox genes control many developmental events along the AP axis, but few target genes have been identified. Whether target genes are activated or repressed, what enhancer elements are required for regulation, and how different domains of the Hox proteins contribute to regulatory specificity is poorly understood. Six2 is genetically downstream of both the Hox11 paralogous genes in the developing mammalian kidney and Hoxa2 in branchial arch and facial mesenchyme. Loss-of-function of Hox11 leads to loss of Six2 expression and loss-of-function of Hoxa2 leads to expanded Six2 expression. Herein we demonstrate that a single enhancer site upstream of the Six2 coding sequence is responsible for both activation by Hox11 proteins in the kidney and repression by Hoxa2 in the branchial arch and facial mesenchyme in vivo. DNA binding activity is required for both activation and repression, but differential activity is not controlled by differences in the homeodomains. Rather, protein domains N- and C-terminal to the homeodomain confer activation versus repression activity. These data support a model in which the DNA binding specificity of Hox proteins in vivo may be similar, consistent with accumulated in vitro data, and that unique functions result mainly from differential interactions mediated by non-homeodomain regions of Hox proteins.

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Section: Resultsmentioning

confidence: 99%

Non-homeodomain regions of Hox proteins mediate activation versus repression of Six2 via a single enhancer site in vivo

Yallowitz

Gong

Swinehart

et al. 2009

Developmental Biology

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“…Moreover, arginine 272 is also conserved in the other family members ALX3 and CART1 . It is a component of the recognition helix 4 of the homeodomain19 and substitution of arginine for proline is likely to disrupt DNA binding also leading to a loss of function. The identification of ALX4 mutations in two of our FPP families now confirms the genetic heterogeneity of FPP.…”

Section: Discussionmentioning

confidence: 99%

The ALX4 homeobox gene is mutated in patients with ossification defects of the skull (foramina parietalia permagna, OMIM 168500)

Wuyts

Cleiren²,

Homfray³

et al. 2000

Journal of Medical Genetics

103

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Foramina parietalia permagna (FPP) (OMIM 168500) is caused by ossification defects in the parietal bones. Recently, it was shown that loss of function mutations in the MSX2 homeobox gene on chromosome 5 are responsible for the presence of these lesions in some FPP patients. However, the absence of MSX2 mutations in some of the FPP patients analysed and the presence of FPP associated with chromosome 11p deletions in DEFECT 11 (OMIM 601224) patients or associated with Saethre-Chotzen syndrome suggests genetic heterogeneity for this disorder. Starting from a BAC/P1/cosmid contig of the DEFECT 11 region on chromosome 11, we have now isolated the ALX4 gene, a previously unidentified member of the ALX homeobox gene family in humans. Mutation analysis of the ALX4 gene in three unrelated FPP families without the MSX2 mutation identified mutations in two families, indicating that mutations in ALX4 could be responsible for these skull defects and suggesting further genetic heterogeneity of FPP. (J Med Genet 2000;37:916-920)

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“…[15][16][17] In the antennapedia, engrailed, and HOXB1 homeodomains, R31 has been found to form a salt bridge with a specific phosphate group in the DNA backbone. 13 14 18 R31 is also predicted to form a salt bridge with a highly conserved glutamate residue at position 42 in helix III. 19 An R31P missense mutation in MSXI, identified in a family with selective tooth agenesis, 20 results in complete loss of protein activity both in vitro and in vivo.…”

Section: R31w Substitution In Hoxd13mentioning

confidence: 99%

Severe digital abnormalities in a patient heterozygous for both a novel missense mutation in HOXD13 and a polyalanine tract expansion in HOXA13

Debeer

2002

Journal of Medical Genetics

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Homeodomain-DNA Recognition

Cited by 109 publications

References 0 publications

Non-homeodomain regions of Hox proteins mediate activation versus repression of Six2 via a single enhancer site in vivo

Non-homeodomain regions of Hox proteins mediate activation versus repression of Six2 via a single enhancer site in vivo

The ALX4 homeobox gene is mutated in patients with ossification defects of the skull (foramina parietalia permagna, OMIM 168500)

Severe digital abnormalities in a patient heterozygous for both a novel missense mutation in HOXD13 and a polyalanine tract expansion in HOXA13

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