Impact of bistrand abasic sites and proximate orientation on DNA global structure and duplex energetics

Conceição A. Minetti, Jeffrey Y. Sun, Daniel P. Jacobs, Inkoo Kang, David P. Remeta, Kenneth Breslauer

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Bistrand lesions embedded within a single helical turn of tridecameric deoxyoligonucleotide duplexes represent a model system for exploring the impact of clustered lesions that occur in vivo and pose a significant challenge to cellular repair machineries. Such investigations are essential for understanding the forces that dictate lesion-induced mutagenesis, carcinogenesis, and cytotoxicity within a context that mimics local helical perturbations caused by an ionizing radiation event. This study characterizes the structural and energy profiles of DNA duplexes harboring synthetic abasic sites (tetrahydrofuran, F) as models of clustered bistrand abasic (AP) lesions. The standard tridecameric dGCGTACCCATGCG·dCGCATGGGTACGC duplex is employed to investigate the energetic impact of single and bistrand AP sites by strategically replacing one or two bases within the central CCC/GGG triplet. Our combined analysis of temperature-dependent UV and circular dichroism (CD) profiles reveals that the proximity and relative orientation of AP sites within bistrand-damaged duplexes imparts a significant thermodynamic impact. Specifically, 3′-staggered lesions (CCF/GFG) exert a greater destabilizing effect when compared with their 5′-counterpart (FCC/GFG). Moreover, a duplex harboring the central bistrand AP lesion (CFC/GFG) is moderately destabilized yet exhibits distinct properties relative to both the 3′ and 5′-orientations. Collectively, our energetic data are consistent with structural studies on bistrand AP-duplexes of similar sequence in which a 3′-staggered lesion exerts the greatest perturbation, a finding that provides significant insight regarding the impact of orientation on lesion repair processing efficiency.

Original languageEnglish (US)
Article numbere23098
JournalBiopolymers
Volume109
Issue number8
DOIs
StatePublished - Aug 1 2018

Fingerprint

Circular Dichroism
Ionizing Radiation
Thermodynamics
Mutagenesis
Carcinogenesis
DNA
Repair
Chlorofluorocarbons
Temperature
Ionizing radiation
Dichroism
Cytotoxicity
Processing
tetrahydrofuran

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Biomaterials
  • Organic Chemistry

Keywords

  • DNA damage
  • bistrand abasic sites
  • clustered lesions
  • thermodynamic stability

Cite this

Minetti, Conceição A. ; Sun, Jeffrey Y. ; Jacobs, Daniel P. ; Kang, Inkoo ; Remeta, David P. ; Breslauer, Kenneth. / Impact of bistrand abasic sites and proximate orientation on DNA global structure and duplex energetics. In: Biopolymers. 2018 ; Vol. 109, No. 8.
@article{92d1a0e26a2b4d298f6eaf165fe55906,
title = "Impact of bistrand abasic sites and proximate orientation on DNA global structure and duplex energetics",
abstract = "Bistrand lesions embedded within a single helical turn of tridecameric deoxyoligonucleotide duplexes represent a model system for exploring the impact of clustered lesions that occur in vivo and pose a significant challenge to cellular repair machineries. Such investigations are essential for understanding the forces that dictate lesion-induced mutagenesis, carcinogenesis, and cytotoxicity within a context that mimics local helical perturbations caused by an ionizing radiation event. This study characterizes the structural and energy profiles of DNA duplexes harboring synthetic abasic sites (tetrahydrofuran, F) as models of clustered bistrand abasic (AP) lesions. The standard tridecameric dGCGTACCCATGCG·dCGCATGGGTACGC duplex is employed to investigate the energetic impact of single and bistrand AP sites by strategically replacing one or two bases within the central CCC/GGG triplet. Our combined analysis of temperature-dependent UV and circular dichroism (CD) profiles reveals that the proximity and relative orientation of AP sites within bistrand-damaged duplexes imparts a significant thermodynamic impact. Specifically, 3′-staggered lesions (CCF/GFG) exert a greater destabilizing effect when compared with their 5′-counterpart (FCC/GFG). Moreover, a duplex harboring the central bistrand AP lesion (CFC/GFG) is moderately destabilized yet exhibits distinct properties relative to both the 3′ and 5′-orientations. Collectively, our energetic data are consistent with structural studies on bistrand AP-duplexes of similar sequence in which a 3′-staggered lesion exerts the greatest perturbation, a finding that provides significant insight regarding the impact of orientation on lesion repair processing efficiency.",
keywords = "DNA damage, bistrand abasic sites, clustered lesions, thermodynamic stability",
author = "Minetti, {Concei{\cc}{\~a}o A.} and Sun, {Jeffrey Y.} and Jacobs, {Daniel P.} and Inkoo Kang and Remeta, {David P.} and Kenneth Breslauer",
year = "2018",
month = "8",
day = "1",
doi = "10.1002/bip.23098",
language = "English (US)",
volume = "109",
journal = "Biopolymers",
issn = "0006-3525",
publisher = "John Wiley and Sons Inc.",
number = "8",

}

Impact of bistrand abasic sites and proximate orientation on DNA global structure and duplex energetics. / Minetti, Conceição A.; Sun, Jeffrey Y.; Jacobs, Daniel P.; Kang, Inkoo; Remeta, David P.; Breslauer, Kenneth.

In: Biopolymers, Vol. 109, No. 8, e23098, 01.08.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Impact of bistrand abasic sites and proximate orientation on DNA global structure and duplex energetics

AU - Minetti, Conceição A.

AU - Sun, Jeffrey Y.

AU - Jacobs, Daniel P.

AU - Kang, Inkoo

AU - Remeta, David P.

AU - Breslauer, Kenneth

PY - 2018/8/1

Y1 - 2018/8/1

N2 - Bistrand lesions embedded within a single helical turn of tridecameric deoxyoligonucleotide duplexes represent a model system for exploring the impact of clustered lesions that occur in vivo and pose a significant challenge to cellular repair machineries. Such investigations are essential for understanding the forces that dictate lesion-induced mutagenesis, carcinogenesis, and cytotoxicity within a context that mimics local helical perturbations caused by an ionizing radiation event. This study characterizes the structural and energy profiles of DNA duplexes harboring synthetic abasic sites (tetrahydrofuran, F) as models of clustered bistrand abasic (AP) lesions. The standard tridecameric dGCGTACCCATGCG·dCGCATGGGTACGC duplex is employed to investigate the energetic impact of single and bistrand AP sites by strategically replacing one or two bases within the central CCC/GGG triplet. Our combined analysis of temperature-dependent UV and circular dichroism (CD) profiles reveals that the proximity and relative orientation of AP sites within bistrand-damaged duplexes imparts a significant thermodynamic impact. Specifically, 3′-staggered lesions (CCF/GFG) exert a greater destabilizing effect when compared with their 5′-counterpart (FCC/GFG). Moreover, a duplex harboring the central bistrand AP lesion (CFC/GFG) is moderately destabilized yet exhibits distinct properties relative to both the 3′ and 5′-orientations. Collectively, our energetic data are consistent with structural studies on bistrand AP-duplexes of similar sequence in which a 3′-staggered lesion exerts the greatest perturbation, a finding that provides significant insight regarding the impact of orientation on lesion repair processing efficiency.

AB - Bistrand lesions embedded within a single helical turn of tridecameric deoxyoligonucleotide duplexes represent a model system for exploring the impact of clustered lesions that occur in vivo and pose a significant challenge to cellular repair machineries. Such investigations are essential for understanding the forces that dictate lesion-induced mutagenesis, carcinogenesis, and cytotoxicity within a context that mimics local helical perturbations caused by an ionizing radiation event. This study characterizes the structural and energy profiles of DNA duplexes harboring synthetic abasic sites (tetrahydrofuran, F) as models of clustered bistrand abasic (AP) lesions. The standard tridecameric dGCGTACCCATGCG·dCGCATGGGTACGC duplex is employed to investigate the energetic impact of single and bistrand AP sites by strategically replacing one or two bases within the central CCC/GGG triplet. Our combined analysis of temperature-dependent UV and circular dichroism (CD) profiles reveals that the proximity and relative orientation of AP sites within bistrand-damaged duplexes imparts a significant thermodynamic impact. Specifically, 3′-staggered lesions (CCF/GFG) exert a greater destabilizing effect when compared with their 5′-counterpart (FCC/GFG). Moreover, a duplex harboring the central bistrand AP lesion (CFC/GFG) is moderately destabilized yet exhibits distinct properties relative to both the 3′ and 5′-orientations. Collectively, our energetic data are consistent with structural studies on bistrand AP-duplexes of similar sequence in which a 3′-staggered lesion exerts the greatest perturbation, a finding that provides significant insight regarding the impact of orientation on lesion repair processing efficiency.

KW - DNA damage

KW - bistrand abasic sites

KW - clustered lesions

KW - thermodynamic stability

UR - http://www.scopus.com/inward/record.url?scp=85040611189&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85040611189&partnerID=8YFLogxK

U2 - 10.1002/bip.23098

DO - 10.1002/bip.23098

M3 - Article

C2 - 29322505

AN - SCOPUS:85040611189

VL - 109

JO - Biopolymers

JF - Biopolymers

SN - 0006-3525

IS - 8

M1 - e23098

ER -