Homeodomain-DNA recognition

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

doi:10.1016/0092-8674(94)90292-5

Cited by 759 publications

(495 citation statements)

References 67 publications

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“…They confer positional identity through the di erential expression of their target genes during embryonic development (Deschamps et al, 1992). The Hox proteins contain a homeobox domain with an extremely well conserved region of 60 ± 61 amino acids that is responsible for sequence speci®c DNA binding (Gehring et al, 1994). For the su cient biological activity, however, the DNA binding of Hox proteins requires several individual interactions with other proteins.…”

Section: Discussionmentioning

confidence: 99%

Cloning and characterization of AFX, the gene that fuses to MLL in acute leukemias with a t(X;11)(q13;q23)

et al. 1997

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We report the cloning and characterization of the entire AFX gene which fuses to MLL in acute leukemias with a t(X;11)(q13;q23). AFX consists of two exons and encodes for a protein of 501 amino acids. We found that normal B-and T-cells contain similar levels of AFX mRNA and that both the MLL/AFX as well as the AFX/MLL fusion transcripts are present in the cell line and the ANLL sample with a t(X;11)(q13;q23). The single intron of the AFX gene consists of 3706 nucleotides. It contains ®ve simple sequence repeats with lengths of at least 12 bps, a chi-like octamer sequence (GCA/TGGA/TGG) and several immunoglobulin heptamer-like sequences (GATAGTG) that are distributed throughout the entire AFX intron sequence. In the KARPAS 45 cell line the breakpoints occur at nucleotides 2913/2914 of the AFX intron and at nucleotides 4900/4901 of the breakpoint cluster region of the MLL gene. The AFX protein belongs to the forkhead protein family. It is highly homologous to the human FKHR protein, the gene of which is disrupted by the t(2;13)(q35;q14), a chromosome rearrangement characteristic of alveolar rhabdomyosarcomas. It is noteworthy that the t(X;11)(q13;q23) in the KARPAS 45 cell line and in one acute nonlymphoblastic leukemia (ANLL) disrupts the forkhead domain of the AFX protein exactly at the same amino acids as does the t(2;13)(q35;q14) in case of the FKHR protein. In addition, the 5'-part of the AFX protein contains a conserved hexapeptide motif (QIYEWM) that is homologous to the functionally important conserved hexapeptide QIYPWM upstream of the homeobox domain in Hox proteins. This motif mediates the co-operative DNA binding of Pbx family members and Hox proteins and, therefore, plays an important role in physiologic and oncogenic processes. In acute leukemias with a t(X;11)(q13;q23), this hexapeptide motif is separated from the remaining forkhead domain within the AFX protein. The predicted amino acid sequence of AFX di ers signi®cantly from the partial AFX protein sequence published previously (Genes, Chromosomes and Cancer, 1994, 11, 79 ± 84). This discrepancy can be explained by the occurrence of two sequencing errors in the earlier work at nucleotide number 783 and 844 (loss of a cytosine residue or guanosine residue, respectively) that lead to two reading frame shifts.

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Section: Discussionmentioning

confidence: 99%

Cloning and characterization of AFX, the gene that fuses to MLL in acute leukemias with a t(X;11)(q13;q23)

et al. 1997

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“…[8] Homedomain proteins (HD) are highly conserved transcription factors that play key roles in eukaryotic development and work by interacting to DNA through a bipartite structure consisting of a helix-turn-helix motif and a minor groove binding N-terminal arm. [9] The major groove DNA contacts are mainly accomplished by the helix 3 of the protein (h3), which, as expected, when isolated from the rest of the protein fails to fold into an alpha-helix structure and bind to its cognate DNA. [10] Considering our previous designs with other DNA binding proteins, we wondered whether tethering of this h3 region of a homedomain to a minor groove binder might suffice for recovering a reasonable DNA interaction.…”

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confidence: 61%

Selective DNA‐Binding by Designed Bisbenzamidine‐Homeodomain Chimeras

et al. 2014

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Abstract:We report the construction of conjugates between several variants of the helix 3 region of a Q50K engrailed homeodomain and bisbenzamidine minor groove DNA binders. While the hybrid featuring the sequence of the native protein fails to bind to DNA, designed modifications that increase the alphahelical folding propensity of the peptide allowed specific DNA binding through a bipartite major-minor groove interaction.

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“…The transcriptional regulators encoded by the Hox genes are believed to be responsible for the establishment of positional information along the anterior-posterior body axis, as well as along the proximodistal and rostral-caudal axis of the limbs (Capecchi, 1996;Krumlauf, 1993Krumlauf, , 1994aMcGinnis and Krumlauf, 1992;Morgan and Tabin, 1993). The 39 vertebrate Hox genes are organized in four clusters on different chromosomes (Kappen and Ruddle, 1993) and share a 180bp homeobox sequence that encodes the highly conserved DNAbinding homeodomain (Gehring et al, 1994).…”

Section: Regionalization Along the Anterior-posterior Axis: Hox Genesmentioning

confidence: 99%

Molecular basis for skeletal variation: insights from developmental genetic studies in mice

Kappen

Neubüser

Balling

et al. 2007

Birth Defects Research Pt B

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Skeletal variations are common in humans, and potentially are caused by genetic as well as environmental factors. We here review molecular principles in skeletal development to develop a knowledge base of possible alterations that could explain variations in skeletal element number, shape or size. Environmental agents that induce variations, such as teratogens, likely interact with the molecular pathways that regulate skeletal development. Birth Defects Res (Part B), 80:425–450, 2007. © 2007 Wiley‐Liss, Inc.

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Homeodomain-DNA recognition

Cited by 759 publications

References 67 publications

Cloning and characterization of AFX, the gene that fuses to MLL in acute leukemias with a t(X;11)(q13;q23)

Cloning and characterization of AFX, the gene that fuses to MLL in acute leukemias with a t(X;11)(q13;q23)

Selective DNA‐Binding by Designed Bisbenzamidine‐Homeodomain Chimeras

Molecular basis for skeletal variation: insights from developmental genetic studies in mice

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