The SKN-1 Amino-Terminal Arm Is a DNA Specificity Segment

Kophengnavong, Thiphaphone; Carroll, Adam S.; Blackwell, T. Keith

doi:10.1128/mcb.19.4.3039

Cited by 21 publications

(17 citation statements)

References 50 publications

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“…As it turns out, the SKN-1 DNA binding region is built around a “souped-up” version of the CNC domain that forms a relatively stable helical structure, along with an additional peptide motif with which SKN-1 recognizes bases in the DNA minor groove (Fig. 1A) [11–15]. SKN-1 therefore binds to its cognate sites on its own with affinity comparable to that of a bZIP dimer [11,12].…”

Section: Background and Overviewmentioning

confidence: 99%

SKN-1/Nrf, stress responses, and aging in Caenorhabditis elegans

Blackwell

Steinbaugh

Hourihan

et al. 2015

Free Radical Biology and Medicine

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467

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The mammalian Nrf/CNC proteins (Nrf1, Nrf2, Nrf3, p45 NF-E2) perform a wide range of cellular protective and maintenance functions. The most thoroughly described of these proteins, Nrf2, is best known as a regulator of antioxidant and xenobiotic defense, but more recently has been implicated in additional functions that include proteostasis and metabolic regulation. In the nematode Caenorhabditis elegans, which offers many advantages for genetic analyses, the Nrf/CNC proteins are represented by their ortholog SKN-1. Although SKN-1 has diverged in aspects of how it binds DNA, it exhibits remarkable functional conservation with Nrf/CNC proteins in other species and regulates many of the same target gene families. C. elegans may therefore have considerable predictive value as a discovery model for understanding how mammalian Nrf/CNC proteins function and are regulated in vivo. Work in C. elegans indicates that SKN-1 regulation is surprisingly complex and is influenced by numerous growth, nutrient, and metabolic signals. SKN-1 is also involved in a wide range of homeostatic functions that extend well beyond the canonical Nrf2 function in responses to acute stress. Importantly, SKN-1 plays a central role in diverse genetic and pharmacologic interventions that promote C. elegans longevity, suggesting that mechanisms regulated by SKN-1 may be of conserved importance in aging. These C. elegans studies predict that mammalian Nrf/CNC protein functions and regulation may be similarly complex and that the proteins and processes that they regulate are likely to have a major influence on mammalian life- and healthspan.

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Section: Background and Overviewmentioning

confidence: 99%

SKN-1/Nrf, stress responses, and aging in Caenorhabditis elegans

Blackwell

Steinbaugh

Hourihan

et al. 2015

Free Radical Biology and Medicine

Self Cite

467

481

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“…Protein expression was carefully quantitated by 35 S-labeled translation and sodium dodecyl sulfatepolyacrylamide gel electrophoresis. These procedures and those for electrophoretic mobility shift assay (EMSA) have been described previously (31). Each EMSA was performed at room temperature and analyzed by autoradiography or phosphorimaging.…”

Section: Methodsmentioning

confidence: 99%

Establishment of Distinct MyoD, E2A, and Twist DNA Binding Specificities by Different Basic Region-DNA Conformations

Kophengnavong

Michnowicz

Blackwell

2000

Molecular and Cellular Biology

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Basic helix-loop-helix (bHLH) proteins perform a wide variety of biological functions. Most bHLH proteins recognize the consensus DNA sequence CAN NTG (the E-box consensus sequence is underlined) but acquire further functional specificity by preferring distinct internal and flanking bases. In addition, induction of myogenesis by MyoD-related bHLH proteins depends on myogenic basic region (BR) and BR-HLH junction residues that are not essential for binding to a muscle-specific site, implying that their BRs may be involved in other critical interactions. We have investigated whether the myogenic residues influence DNA sequence recognition and how MyoD, Twist, and their E2A partner proteins prefer distinct CAN NTG sites. In MyoD, the myogenic BR residues establish specificity for particular CAN NTG sites indirectly, by influencing the conformation through which the BR helix binds DNA. An analysis of DNA binding by BR and junction mutants suggests that an appropriate BR-DNA conformation is necessary but not sufficient for myogenesis, supporting the model that additional interactions with this region are important. The sequence specificities of E2A and Twist proteins require the corresponding BR residues. In addition, mechanisms that position the BR allow E2A to prefer distinct half-sites as a heterodimer with MyoD or Twist, indicating that the E2A BR can be directed toward different targets by dimerization with different partners. Our findings indicate that E2A and its partner bHLH proteins bind to CAN NTG sites by adopting particular preferred BR-DNA conformations, from which they derive differences in sequence recognition that can be important for functional specificity.

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“…SKN-1 lacks a ZIP segment, which is essential for bZIP protein DNA binding because it acts as a dimerization element, and stabilizes folding of the BR on the DNA (Talanian et al 1990). In contrast, monomeric SKN-1 DNA binding is comparably stabilized by a flexible "arm" that binds in the minor groove, and by a novel variant of the CNC region, through which SKN-1 is distantly related to a bZIP protein subgroup (Blackwell et al 1994;Carroll et al 1997;Kophengnavong et al 1999). SKN-1 is also similar to two vertebrate CNC-group proteins (NF-E2-related factors Nrf1 and Nrf2) within a 14-amino-acid transactivator element (DIDLID; Fig.…”

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confidence: 99%

SKN-1 linksC. elegansmesendodermal specification to a conserved oxidative stress response

An¹,

Blackwell²

2003

Genes Dev.

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877

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During the earliest stages of Caenorhabditis elegans embryogenesis, the transcription factor SKN-1 initiates development of the digestive system and other mesendodermal tissues. Postembryonic SKN-1 functions have not been elucidated. SKN-1 binds to DNA through a unique mechanism, but is distantly related to basic leucine-zipper proteins that orchestrate the major oxidative stress response in vertebrates and yeast. Here we show that despite its distinct mode of target gene recognition, SKN-1 functions similarly to resist oxidative stress in C. elegans. During postembryonic stages, SKN-1 regulates a key Phase II detoxification gene through constitutive and stress-inducible mechanisms in the ASI chemosensory neurons and intestine, respectively. SKN-1 is present in ASI nuclei under normal conditions, and accumulates in intestinal nuclei in response to oxidative stress. skn-1 mutants are sensitive to oxidative stress and have shortened lifespans. SKN-1 represents a connection between developmental specification of the digestive system and one of its most basic functions, resistance to oxidative and xenobiotic stress. This oxidative stress response thus appears to be both widely conserved and ancient, suggesting that the mesendodermal specification role of SKN-1 was predated by its function in these detoxification mechanisms.

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The SKN-1 Amino-Terminal Arm Is a DNA Specificity Segment

Cited by 21 publications

References 50 publications

SKN-1/Nrf, stress responses, and aging in Caenorhabditis elegans

SKN-1/Nrf, stress responses, and aging in Caenorhabditis elegans

Establishment of Distinct MyoD, E2A, and Twist DNA Binding Specificities by Different Basic Region-DNA Conformations

SKN-1 linksC. elegansmesendodermal specification to a conserved oxidative stress response

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