Distinct Molecular Strategies for Hox-Mediated Limb Suppression in Drosophila: From Cooperativity to Dispensability/Antagonism in TALE Partnership

Sambrani, Nagraj; Hudry, Bruno; Maurel-Zaffran, Corinne; Zouaz, Amel; Mishra, Rakesh K.; Merabet, Samir; Graba, Yacine

doi:10.1371/journal.pgen.1003307

Cited by 21 publications

(39 citation statements)

References 53 publications

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“…This strong loss of repressive activity does not result from impaired DNA binding as shown by the maintained ability of Ubx KQE>AAA to activate dpp ( Figure S2). In addition, a DNA binding-deficient Ubx protein was previously shown to repress Dll more efficiently (65% of repressive potential) than Ubx KQE>AAA (Sambrani et al, 2013), further arguing that the effect of the KQE>AAA mutation can not be explained by a loss of DNA binding.…”

Section: Structure-identified Ubda-exd Contacts Contribute To the Assmentioning

confidence: 99%

A Flexible Extension of the Drosophila Ultrabithorax Homeodomain Defines a Novel Hox/PBC Interaction Mode

et al. 2015

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The patterning function of Hox proteins relies on assembling protein complexes with PBC proteins, which often involves a protein motif found in most Hox proteins, the so-called Hexapeptide (HX). Hox/PBC complexes likely gained functional diversity by acquiring additional modes of interaction. Here, we structurally characterize the first HX alternative interaction mode based on the paralogue-specific UbdA motif and further functionally validate structure-based predictions. The UbdA motif folds as a flexible extension of the homeodomain recognition helix and defines Hox/PBC contacts that occur, compared with those mediated by the HX motif, on the opposing side of the DNA double helix. This provides a new molecular facet to Hox/PBC complex assembly and suggests possible mechanisms for the diversification of Hox protein function.

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Section: Structure-identified Ubda-exd Contacts Contribute To the Assmentioning

confidence: 99%

A Flexible Extension of the Drosophila Ultrabithorax Homeodomain Defines a Novel Hox/PBC Interaction Mode

et al. 2015

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“…This regulation often, but not always, depends on the TALE cofactors [14,16], illustrating the diversity of the underlying molecular mechanisms (see also below). Along the same lines, other target genes might be regulated by even more, or in principle all, Hox paralogs and are referred to as paralog non-specific 12,17] (Figure 2). …”

Section: Flavors Of Hox-tale Target Genesmentioning

confidence: 99%

To Be Specific or Not: The Critical Relationship Between Hox And TALE Proteins

2016

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Hox proteins are key regulatory transcription factors that act in different tissues of the embryo to provide specific spatial and temporal coordinates to each cell. These patterning functions often depend on the presence of the TALE-homeodomain class cofactors, which form cooperative DNA-binding complexes with all Hox proteins. How this family of cofactors contributes to the highly diverse and specific functions of Hox proteins in vivo remains an important unsolved question. Here we review the most recent advances in understanding the molecular mechanisms underlying Hox-TALE function. In particular, we discuss the role of DNA shape, DNA- binding affinity and protein-protein interaction flexibility in dictating Hox-TALE specificity. We propose several models to explain how these mechanisms are integrated with each other in the context of the many distinct functions Hox and TALE factors carry out in vivo.

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“…Indeed, the majority of sites co-bound by HOX and PBX proteins show histone H3 K27 acetylation and not trimethylation, suggesting that complexes containing HOX/PBX may be primarily transcriptional activators (99). Additional studies have established that interactions with TALE cofactors are not required at some loci and HOX proteins themselves may homo or heterodimerize at these sites (117). Furthermore, there is new evidence of antagonism between TALE proteins and HOX proteins at specific genomic regions (118).…”

Section: Mechanisms Of Hoxa9-regulated Gene Transcriptionmentioning

confidence: 99%

Role of HOXA9 in leukemia: dysregulation, cofactors and essential targets

2015

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HOXA9 is a homeodomain-containing transcription factor that plays an important role in hematopoietic stem cell expansion and is commonly deregulated in acute leukemias. A variety of upstream genetic alterations in acute myeloid leukemia (AML) lead to overexpression of HOXA9, which is a strong predictor of poor prognosis. In many cases, HOXA9 has been shown to be necessary for maintaining leukemic transformation, however the molecular mechanisms through which it promotes leukemogenesis remain elusive. Recent work has established that HOXA9 regulates downstream gene expression through binding at promoter distal enhancers along with a subset of cell-specific cofactor and collaborator proteins. Increasing efforts are being made to identify both the critical cofactors and target genes required for maintaining transformation in HOXA9-overexpressing leukemias. With continued advances in understanding HOXA9-mediated transformation, there is a wealth of opportunity for developing novel therapeutics that would be applicable for the greater than 50% of AML with overexpression of HOXA9.

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Distinct Molecular Strategies for Hox-Mediated Limb Suppression in Drosophila: From Cooperativity to Dispensability/Antagonism in TALE Partnership

Cited by 21 publications

References 53 publications

A Flexible Extension of the Drosophila Ultrabithorax Homeodomain Defines a Novel Hox/PBC Interaction Mode

A Flexible Extension of the Drosophila Ultrabithorax Homeodomain Defines a Novel Hox/PBC Interaction Mode

To Be Specific or Not: The Critical Relationship Between Hox And TALE Proteins

Role of HOXA9 in leukemia: dysregulation, cofactors and essential targets

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