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Article: The Non-continuum Nature of Eukaryotic Transcriptional Regulation.

Poon, Gregory M K

Advances in experimental medicine and biology

2021 Volume 1371, Page(s) 11–32

Abstract: Eukaryotic transcription factors are versatile mediators of specificity in gene regulation. This versatility is achieved through mutual specification by context-specific DNA binding on the one hand, and identity-specific protein-protein partnerships on ... ...

Abstract	Eukaryotic transcription factors are versatile mediators of specificity in gene regulation. This versatility is achieved through mutual specification by context-specific DNA binding on the one hand, and identity-specific protein-protein partnerships on the other. This interactivity, known as combinatorial control, enables a repertoire of complex transcriptional outputs that are qualitatively disjoint, or non-continuum, with respect to binding affinity. This feature contrasts starkly with prokaryotic gene regulators, whose activities in general vary quantitatively in step with binding affinity. Biophysical studies on prokaryotic model systems and more recent investigations on transcription factors highlight an important role for folded state dynamics and molecular hydration in protein/DNA recognition. Analysis of molecular models of combinatorial control and recent literature in low-affinity gene regulation suggest that transcription factors harbor unique conformational dynamics that are inaccessible or unused by prokaryotic DNA-binding proteins. Thus, understanding the intrinsic dynamics involved in DNA binding and co-regulator recruitment appears to be a key to understanding how transcription factors mediate non-continuum outcomes in eukaryotic gene expression, and how such capability might have evolved from ancient, structurally conserved counterparts.
MeSH term(s)	DNA-Binding Proteins/genetics ; Eukaryota/genetics ; Eukaryota/metabolism ; Eukaryotic Cells/metabolism ; Gene Expression Regulation ; Transcription Factors/metabolism
Chemical Substances	DNA-Binding Proteins ; Transcription Factors
Language	English
Publishing date	2021-02-19
Publishing country	United States
Document type	Journal Article
ISSN	2214-8019 ; 0065-2598
ISSN (online)	2214-8019
ISSN	0065-2598
DOI	10.1007/5584_2021_618
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Article ; Online: Detecting recurrent passenger mutations in melanoma by targeted UV damage sequencing.

Selvam, Kathiresan / Sivapragasam, Smitha / Poon, Gregory M K / Wyrick, John J

Nature communications

2023 Volume 14, Issue 1, Page(s) 2702

Abstract: Sequencing of melanomas has identified hundreds of recurrent mutations in both coding and non-coding DNA. These include a number of well-characterized oncogenic driver mutations, such as coding mutations in the BRAF and NRAS oncogenes, and non-coding ... ...

Abstract	Sequencing of melanomas has identified hundreds of recurrent mutations in both coding and non-coding DNA. These include a number of well-characterized oncogenic driver mutations, such as coding mutations in the BRAF and NRAS oncogenes, and non-coding mutations in the promoter of telomerase reverse transcriptase (TERT). However, the molecular etiology and significance of most of these mutations is unknown. Here, we use a new method known as CPD-capture-seq to map UV-induced cyclobutane pyrimidine dimers (CPDs) with high sequencing depth and single nucleotide resolution at sites of recurrent mutations in melanoma. Our data reveal that many previously identified drivers and other recurrent mutations in melanoma occur at CPD hotspots in UV-irradiated melanocytes, often associated with an overlapping binding site of an E26 transformation-specific (ETS) transcription factor. In contrast, recurrent mutations in the promoters of a number of known or suspected cancer genes are not associated with elevated CPD levels. Our data indicate that a subset of recurrent protein-coding mutations are also likely caused by ETS-induced CPD hotspots. This analysis indicates that ETS proteins profoundly shape the mutation landscape of melanoma and reveals a method for distinguishing potential driver mutations from passenger mutations whose recurrence is due to elevated UV damage.
MeSH term(s)	Humans ; Melanoma/genetics ; Melanoma/metabolism ; Mutation ; Pyrimidine Dimers/genetics ; DNA Damage ; Melanocytes/metabolism ; Ultraviolet Rays/adverse effects ; Skin Neoplasms/genetics
Chemical Substances	Pyrimidine Dimers
Language	English
Publishing date	2023-05-11
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-38265-3
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Article ; Online: Dissecting knowledge, guessing, and blunder in multiple choice assessments.

Abu-Ghazalah, Rashid M / Dubins, David N / Poon, Gregory M K

Applied measurement in education

2023 Volume 36, Issue 1, Page(s) 80–98

Abstract: Multiple choice results are inherently probabilistic outcomes, as correct responses reflect a combination of knowledge and guessing, while incorrect responses additionally reflect blunder, a confidently committed mistake. To objectively resolve knowledge ...

Abstract	Multiple choice results are inherently probabilistic outcomes, as correct responses reflect a combination of knowledge and guessing, while incorrect responses additionally reflect blunder, a confidently committed mistake. To objectively resolve knowledge from responses in an MC test structure, we evaluated probabilistic models that explicitly account for guessing, knowledge and blunder using eight assessments (>9,000 responses) from an undergraduate biotechnology curriculum. A Bayesian implementation of the models, aimed at assessing their robustness to prior beliefs in examinee knowledge, showed that explicit estimators of knowledge are markedly sensitive to prior beliefs with scores as sole input. To overcome this limitation, we examined self-ranked confidence as a proxy knowledge indicator. For our test set, three levels of confidence resolved test performance. Responses rated as least confident were correct more frequently than expected from random selection, reflecting partial knowledge, but were balanced by blunder among the most confident responses. By translating evidence-based guessing and blunder rates to pass marks that statistically qualify a desired level of examinee knowledge, our approach finds practical utility in test analysis and design.
Language	English
Publishing date	2023-02-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	2008021-9
ISSN	1532-4818 ; 0895-7347
ISSN (online)	1532-4818
ISSN	0895-7347
DOI	10.1080/08957347.2023.2172017
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Article: Molecular mechanism of UV damage modulation in nucleosomes.

Stark, Bastian / Poon, Gregory M K / Wyrick, John J

Computational and structural biotechnology journal

2022 Volume 20, Page(s) 5393–5400

Abstract: Exposure to ultraviolet (UV) light causes the formation of mutagenic cyclobutane pyrimidine dimers (CPDs) in cellular DNA. Previous studies have revealed that CPD formation in nucleosomes, the building blocks of chromatin, shows a striking ∼10 base pair ( ...

Abstract	Exposure to ultraviolet (UV) light causes the formation of mutagenic cyclobutane pyrimidine dimers (CPDs) in cellular DNA. Previous studies have revealed that CPD formation in nucleosomes, the building blocks of chromatin, shows a striking ∼10 base pair (bp) periodic pattern. CPD formation is suppressed at positions where the DNA minor groove faces toward the histone octamer (minor-in) and elevated CPD formation at positions where the minor groove faces away from the histone octamer (minor-out). However, the molecular mechanism underlying this nucleosome photofootprint is unclear. Here, we analyzed ∼180 high-resolution nucleosome structures to characterize whether differences in DNA mobility or conformation are responsible for the CPD modulation in nucleosomes. Our results indicate that differences in DNA mobility cannot explain CPD modulation in nucleosome. Instead, we find that the sharp DNA bending around the histone octamer results in DNA conformations with structural parameters more susceptible to UV damage formation at minor-out positions and more resistant to CPD formation at minor-in positions. This analysis reveals the molecular mechanism responsible for periodic modulation of CPD formation and UV mutagenesis in nucleosomal DNA.
Language	English
Publishing date	2022-09-14
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2694435-2
ISSN	2001-0370
ISSN	2001-0370
DOI	10.1016/j.csbj.2022.08.071
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Article: CTCF puts a new twist on UV damage and repair in skin cancer.

Stark, Bastian / Poon, Gregory M K / Wyrick, John J

Molecular & cellular oncology

2021 Volume 8, Issue 6, Page(s) 2009424

Abstract: Somatic mutations in skin cancers are highly enriched at binding sites for CCCTC-binding factor (CTCF). We have discovered that CTCF binding alters the DNA structure to render it more susceptible to UV damage. Elevated UV damage formation at CTCF binding ...

Abstract	Somatic mutations in skin cancers are highly enriched at binding sites for CCCTC-binding factor (CTCF). We have discovered that CTCF binding alters the DNA structure to render it more susceptible to UV damage. Elevated UV damage formation at CTCF binding sites, in conjunction with subsequent repair inhibition, promotes UV mutagenesis.
Language	English
Publishing date	2021-12-06
Publishing country	United States
Document type	Journal Article
ISSN	2372-3556
ISSN	2372-3556
DOI	10.1080/23723556.2021.2009424
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Article: Title: “Molecular Mechanism of UV Damage Modulation in Nucleosomes”

Stark, Bastian / Poon, Gregory M.K. / Wyrick, John J.

Computational and Structural Biotechnology Journal. 2022 Aug. 31,

2022

Abstract	Exposure to ultraviolet (UV) light causes the formation of mutagenic cyclobutane pyrimidine dimers (CPDs) in cellular DNA. Previous studies have revealed that CPD formation in nucleosomes, the building blocks of chromatin, shows a striking ∼10 base pair (bp) periodic pattern. CPD formation is suppressed at positions where the DNA minor groove faces toward the histone octamer (minor-in) and elevated CPD formation at positions where the minor groove faces away from the histone octamer (minor-out). However, the molecular mechanism underlying this nucleosome photofootprint is unclear. Here, we analyzed ∼180 high-resolution nucleosome structures to characterize whether differences in DNA mobility or conformation are responsible for the CPD modulation in nucleosomes. Our results indicate that differences in DNA mobility cannot explain CPD modulation in nucleosome. Instead, we find that the sharp DNA bending around the histone octamer results in DNA conformations with structural parameters more susceptible to UV damage formation at minor-out positions and more resistant to CPD formation at minor-in positions. This analysis reveals the molecular mechanism responsible for periodic modulation of CPD formation and UV mutagenesis in nucleosomal DNA.
Keywords	DNA ; biotechnology ; histones ; mutagenesis ; mutagens ; nucleosomes
Language	English
Dates of publication	2022-0831
Publishing place	Elsevier B.V.
Document type	Article
Note	Pre-press version
ZDB-ID	2694435-2
ISSN	2001-0370
ISSN	2001-0370
DOI	10.1016/j.csbj.2022.08.071
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Article: Self-Consistent Parameterization of DNA Residues for the Non-Polarizable AMBER Force Fields.

Schneider, Amelia L / Albrecht, Amanda V / Huang, Kenneth / Germann, Markus W / Poon, Gregory M K

Life (Basel, Switzerland)

2022 Volume 12, Issue 5

Abstract: Fixed-charge (non-polarizable) forcefields are accurate and computationally efficient tools for modeling the molecular dynamics of nucleic acid polymers, particularly DNA, well into the µs timescale. The continued utility of these forcefields depends in ... ...

Abstract	Fixed-charge (non-polarizable) forcefields are accurate and computationally efficient tools for modeling the molecular dynamics of nucleic acid polymers, particularly DNA, well into the µs timescale. The continued utility of these forcefields depends in part on expanding the residue set in step with advancing nucleic acid chemistry and biology. A key step in parameterizing new residues is charge derivation which is self-consistent with the existing residues. As atomic charges are derived by fitting against molecular electrostatic potentials, appropriate structural models are critical. Benchmarking against the existing charge set used in current AMBER nucleic acid forcefields, we report that quantum mechanical models of deoxynucleosides, even at a high level of theory, are not optimal structures for charge derivation. Instead, structures from molecular mechanics minimization yield charges with up to 6-fold lower RMS deviation from the published values, due to the choice of such an approach in the derivation of the original charge set. We present a contemporary protocol for rendering self-consistent charges as well as optimized charges for a panel of nine non-canonical residues that will permit comparison with literature as well as studying the dynamics of novel DNA polymers.
Language	English
Publishing date	2022-04-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662250-6
ISSN	2075-1729
ISSN	2075-1729
DOI	10.3390/life12050666
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Article ; Online: Dissection of integrated readout reveals the structural thermodynamics of DNA selection by transcription factors.

Vernon, Tyler N / Terrell, J Ross / Albrecht, Amanda V / Germann, Markus W / Wilson, W David / Poon, Gregory M K

Structure (London, England : 1993)

2023 Volume 32, Issue 1, Page(s) 83–96.e4

Abstract: Nucleobases such as inosine have been extensively utilized to map direct contacts by proteins in the DNA groove. Their deployment as targeted probes of dynamics and hydration, which are dominant thermodynamic drivers of affinity and specificity, has been ...

Abstract	Nucleobases such as inosine have been extensively utilized to map direct contacts by proteins in the DNA groove. Their deployment as targeted probes of dynamics and hydration, which are dominant thermodynamic drivers of affinity and specificity, has been limited by a paucity of suitable experimental models. We report a joint crystallographic, thermodynamic, and computational study of the bidentate complex of the arginine side chain with a Watson-Crick guanine (Arg×GC), a highly specific configuration adopted by major transcription factors throughout the eukaryotic branches in the Tree of Life. Using the ETS-family factor PU.1 as a high-resolution structural framework, inosine substitution for guanine resulted in a sharp dissection of conformational dynamics and hydration and elucidated their role in the DNA specificity of PU.1. Our work suggests an under-exploited utility of modified nucleobases in untangling the structural thermodynamics of interactions, such as the Arg×GC motif, where direct and indirect readout are tightly integrated.
MeSH term(s)	Transcription Factors/metabolism ; Binding Sites ; Protein Binding ; Proto-Oncogene Proteins/chemistry ; Thermodynamics ; DNA/metabolism ; Guanine ; Inosine/metabolism ; Nucleic Acid Conformation
Chemical Substances	Transcription Factors ; Proto-Oncogene Proteins ; DNA (9007-49-2) ; Guanine (5Z93L87A1R) ; Inosine (5A614L51CT)
Language	English
Publishing date	2023-12-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	1213087-4
ISSN	1878-4186 ; 0969-2126
ISSN (online)	1878-4186
ISSN	0969-2126
DOI	10.1016/j.str.2023.11.003
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Article: DNA-facilitated target search by nucleoproteins: Extension of a biosensor-surface plasmon resonance method

Vo, Tam D. / Schneider, Amelia L. / Poon, Gregory M.K. / Wilson, W. David

Analytical biochemistry. 2021 Sept. 15, v. 629

2021

Abstract: To extend the value of biosensor-SPR in the characterization of DNA recognition by nucleoproteins, we report a comparative analysis of DNA-facilitated target search by two ETS-family transcription factors: Elk1 and ETV6. ETS domains represent an ... ...

Abstract	To extend the value of biosensor-SPR in the characterization of DNA recognition by nucleoproteins, we report a comparative analysis of DNA-facilitated target search by two ETS-family transcription factors: Elk1 and ETV6. ETS domains represent an attractive system for developing biosensor-based techniques due to a broad range of physicochemical properties encoded within a highly conserved DNA-binding motif. Building on a biosensor approach in which the protein is quantitatively sequestered and presented to immobilized cognate DNA as nonspecific complexes, we assessed the impact of intrinsic cognate and nonspecific affinities on long-range (intersegmental) target search. The equilibrium constants of DNA-facilitated binding were sensitive to the intrinsic binding properties of the proteins such that their relative specificity for cognate DNA were reinforced when binding occurred by transfer vs. without nonspecific DNA. Direct measurement of association and dissociation kinetics revealed ionic features of the activated complex that evidenced DNA-facilitated dissociation, even though Elk1 and ETV6 harbor only a single DNA-binding surface. At salt concentrations that masked the effects of nonspecific pre-binding at equilibrium, the dissociation kinetics of cognate binding were nevertheless distinct from conditions under which nonspecific DNA was absent. These results further strengthen the significance of long-range DNA-facilitated translocation in the physiologic environment.
Keywords	DNA ; biosensors ; dissociation ; nucleoproteins
Language	English
Dates of publication	2021-0915
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	1110-1
ISSN	1096-0309 ; 0003-2697
ISSN (online)	1096-0309
ISSN	0003-2697
DOI	10.1016/j.ab.2021.114298
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Article ; Online: Salt bridge dynamics in protein/DNA recognition: a comparative analysis of Elk1 and ETV6.

Vo, Tam D / Schneider, Amelia L / Wilson, W David / Poon, Gregory M K

Physical chemistry chemical physics : PCCP

2021 Volume 23, Issue 24, Page(s) 13490–13502

Abstract: Electrostatic protein/DNA interactions arise from the neutralization of the DNA phosphodiester backbone as well as coupled exchanges by charged protein residues as salt bridges or with mobile ions. Much focus has been and continues to be paid to ... ...

Abstract	Electrostatic protein/DNA interactions arise from the neutralization of the DNA phosphodiester backbone as well as coupled exchanges by charged protein residues as salt bridges or with mobile ions. Much focus has been and continues to be paid to interfacial ion pairs with DNA. The role of extra-interfacial ionic interactions, particularly as dynamic drivers of DNA sequence selectivity, remain poorly known. The ETS family of transcription factors represents an attractive model for addressing this knowledge gap given their diverse ionic composition in primary structures that fold to a tightly conserved DNA-binding motif. To probe the importance of extra-interfacial salt bridges in DNA recognition, we compared the salt-dependent binding by Elk1 with ETV6, two ETS homologs differing markedly in ionic composition. While both proteins exhibit salt-dependent binding with cognate DNA that corresponds to interfacial phosphate contacts, their nonspecific binding diverges from cognate binding as well as each other. Molecular dynamics simulations in explicit solvent, which generated ionic interactions in agreement with the experimental binding data, revealed distinct salt-bridge dynamics in the nonspecific complexes formed by the two proteins. Impaired DNA contact by ETV6 resulted in fewer backbone contacts in the nonspecific complex, while Elk1 exhibited a redistribution of extra-interfacial salt bridges via residues that are non-conserved between the two ETS relatives. Thus, primary structure variation in ionic residues can encode highly differentiated specificity mechanisms in a highly conserved DNA-binding motif.
MeSH term(s)	DNA/chemistry ; Density Functional Theory ; Humans ; Molecular Dynamics Simulation ; Proto-Oncogene Proteins c-ets/chemistry ; Repressor Proteins/chemistry ; ets-Domain Protein Elk-1/chemistry ; ETS Translocation Variant 6 Protein
Chemical Substances	ELK1 protein, human ; Proto-Oncogene Proteins c-ets ; Repressor Proteins ; ets-Domain Protein Elk-1 ; DNA (9007-49-2)
Language	English
Publishing date	2021-06-13
Publishing country	England
Document type	Comparative Study ; Journal Article
ZDB-ID	1476244-4
ISSN	1463-9084 ; 1463-9076
ISSN (online)	1463-9084
ISSN	1463-9076
DOI	10.1039/d1cp01568k
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