Evaluation of Sox2 binding affinities for distinct <scp>DNA</scp> patterns using steered molecular dynamics simulation

Yesudhas, Dhanusha; Anwar, Muhammad Ayaz; Suresh, Paladugu; Kim, Han-Kyul; Choi, Sangdun

doi:10.1002/2211-5463.12316

Cited by 20 publications

(17 citation statements)

References 61 publications

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“…Our result is compliant with previous reports, finding Sp2 a weak activator with little or no capacity for additive or synergistic transactivation (65). The Sp2 was reported to specifically bind DNA, occupies distal enhancer elements (68)(69)(70) and functions as repressor (67). Differently, human Sp1 and Sp3 were reported as activators of transcription (71)(72)(73).…”

Section: Figure S2supporting

confidence: 90%

The evolution of the 9aaTAD domain in Sp2 proteins: inactivation with valines and intron reservoirs

Piskáček

Havelka

Jendruchova

et al. 2019

Preprint

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The Sp1 transcription factor has been defined as glutamine-rich activator. The Nine amino acid TransActivation Domains (9aaTAD) have been identified in numerous transcription activators. Here, we identified the conserved 9aaTAD motif in the Sp1 and in all nine members of SP family with broad natural 9aaTAD variations. We showed by the amino acid substitutions that the glutamine residues are completely dispensable for 9aaTADs function. We described the 9aaTAD domains' origin and evolutionary history. The ancestral Sp2 gene with inactive 9aaTAD has duplicated in early chordates and created new paralogs Sp1, Sp3 and Sp4. We discovered that the accumulation of valines in the 9aaTADs correlated with the domain inactivation. The Sp2 activation domain, whose dormancy have lasted over 100 million years during chordate evolution, enabled later diversification in the Sp1-4 clade, including both repressors and activators. The new paralogs Sp1 and Sp3 activation domains have regained their original activator function by loss of valines in their 9aaTADs.Keywords: activation domain, 9aaTAD, SP, Sp1, KLF, WT1, Gal4, Met4, Gcn4 and p53. demonstrated the importance of the hydrophobic amino acids for Gcn4 (30-33) and p53 activators (8,(34)(35)(36)(37)(38)(39)(40). Similarly, in the original report for the glutamine-rich activator Sp1(41), the importance of hydrophobic amino acids was already recognized, regardless of the overrepresented glutamines.Nevertheless, the designation as acidic or glutamine-rich activation domains persists to date (42-49).In the human genome, there are about 1,691 annotated transcription factors, divided into 68 groups according to their conserved DNA binding domain (50). The C2H2-type zinc finger is the largest group (682 members), which includes the evolutionally conserved family of KLF activators (Krüppel-like factors). The SP activators (Specificity proteins Sp1-9) belong to a new evolutional branch derived from the ancestral KLF family. The SP activators have been linked to cell proliferation, embryonic development, tissue differentiation, Wnt signaling pathway, metabolism, and their dysregulation has been implicated in a number of human diseases and cancers (51)(52)(53)(54)(55)(56). This report has focused on the SP family and followed the 9aaTAD domain's evolution. MATERIALS AND METHODSConstructs. The construct pBTM116-HA was generated by an insertion of the HA cassette into the EcoRI site of the vector pBTM116. The constructs G1-G45 and H1-H45 were generated by PCR and sub-cloned into pBTM116 EcoRI and BamHI sites. All constructs have a spacer of three amino acids inserted into the EcoRI site; peptide GSG. All constructs have been sequenced by Eurofins Genomics.Further detailed information about constructs and primer sequences are available on request.Assessment of enzyme activities. The β-galactosidase activity was determined in the yeast strain L40 (57,58). The strain L40 has a chromosomally integrated lacZ reporter driven by the lexA operator. In all hybrid assays, we used 2μ vector pBTM116 for...

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Section: Figure S2supporting

confidence: 90%

The evolution of the 9aaTAD domain in Sp2 proteins: inactivation with valines and intron reservoirs

Piskáček

Havelka

Jendruchova

et al. 2019

Preprint

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“…Although SOX2 unquestionably interacts with DNA [ 26 , 38 , 39 ], a direct causal assignment of individual target genes with distinct functional manifestations remains difficult. Indeed, while the human genome comprises several thousand potential docking sites for SOX2, as predicted by an in silico search in advanced human glioma cells [ 40 ], an effective association with no more than 489 protein coding genes and 105 pre-miRNAs was experimentally determined by ChIP-seq [ 40 ].…”

Section: Molecular–functional Aspects Of Sox2-imposed Stemnessmentioning

confidence: 99%

SOX2 and p53 Expression Control Converges in PI3K/AKT Signaling with Versatile Implications for Stemness and Cancer

Schaefer

Steiner

Lengerke

2020

IJMS

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Stemness and reprogramming involve transcriptional master regulators that suppress cell differentiation while promoting self-renewal. A distinguished example thereof is SOX2, a high mobility group (HMG)-box transcription factor (TF), whose subcellular localization and turnover regulation in embryonic, induced-pluripotent, and cancer stem cells (ESCs, iPSCs, and CSCs, respectively) is mediated by the PI3K/AKT/SOX2 axis, a stem cell-specific branch of the PI3K/AKT signaling pathway. Further effector functions associated with PI3K/AKT induction include cell cycle progression, cellular (mass) growth, and the suppression of apoptosis. Apoptosis, however, is a central element of DNA damage response (DDR), where it provides a default mechanism for cell clearance when DNA integrity cannot be maintained. A key player in DDR is tumor suppressor p53, which accumulates upon DNA-damage and is counter-balanced by PI3K/AKT enforced turnover. Accordingly, stemness sustaining SOX2 expression and p53-dependent DDR mechanisms show molecular–functional overlap in PI3K/AKT signaling. This constellation proves challenging for stem cells whose genomic integrity is a functional imperative for normative ontogenesis. Unresolved mutations in stem and early progenitor cells may in fact provoke transformation and cancer development. Such mechanisms are also particularly relevant for iPSCs, where genetic changes imposed through somatic cell reprogramming may promote DNA damage. The current review aims to summarize the latest advances in the understanding of PI3K/AKT/SOX2-driven stemness and its intertwined relations to p53-signaling in DDR under conditions of pluripotency, reprogramming, and transformation.

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“…By contrast, the HMG/DNA-interaction has been resolved in considerable detail and a DNA recognition consensus long been defined for SOX2/Sox2 (i.e., CCCATTGTTC in man and CTTTGTC in mouse) [13,14]. However, with the central TTGT element being the preferred recognition motif of all SOX/Sox proteins and several thousand copies of the extended consensus in the human genome, SOX2 resembles a rather promiscuous transcription factor.…”

Section: An Introduction To Sox2 and Underexplored Aspects Of Its Molmentioning

confidence: 99%

SOX2 protein biochemistry in stemness, reprogramming, and cancer: the PI3K/AKT/SOX2 axis and beyond

2019

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Research of the past view years expanded our understanding of the various physiological functions the cell-fate determining transcription factor SOX2 exerts in ontogenesis, reprogramming, and cancer. However, while scientific reports featuring novel and exciting aspects of SOX2-driven biology are published in near weekly routine, investigations in the underlying protein-biochemical processes that transiently tailor SOX2 activity to situational demand are underrepresented and have not yet been comprehensively summarized. Largely unrecognizable to modern array or sequencing-based technology, various protein secondary modifications and concomitant function modulations have been reported for SOX2. The chemical modifications imposed onto SOX2 are inherently heterogeneous, comprising singular or clustered events of phosphorylation, methylation, acetylation, ubiquitination, SUMOylation, PARPylation, and O-glycosylation that reciprocally affect each other and critically impact SOX2 functionality, often in a tissue and species-specific manner. One recurring regulatory principle though is the canonical PI3K/AKT signaling axis to which SOX2 relates in various entangled, albeit not exclusive ways. Here we provide a comprehensive review of the current knowledge on SOX2 protein modifications, their proposed relationship to the PI3K/AKT pathway, and regulatory influence on SOX2 with regards to stemness, reprogramming, and cancer.

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Evaluation of Sox2 binding affinities for distinct DNA patterns using steered molecular dynamics simulation

Cited by 20 publications

References 61 publications

The evolution of the 9aaTAD domain in Sp2 proteins: inactivation with valines and intron reservoirs

The evolution of the 9aaTAD domain in Sp2 proteins: inactivation with valines and intron reservoirs

SOX2 and p53 Expression Control Converges in PI3K/AKT Signaling with Versatile Implications for Stemness and Cancer

SOX2 protein biochemistry in stemness, reprogramming, and cancer: the PI3K/AKT/SOX2 axis and beyond

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