Recognition of platinum-DNA adducts by HMGB1a

Srinivas Ramachandran, Brenda Temple, Anastassia N. Alexandrova, Stephen G. Chaney, Nikolay Dokholyan

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Cisplatin (CP) and oxaliplatin (OX), platinum-based drugs used widely in chemotherapy, form adducts on intrastrand guanines (5′GG) in genomic DNA. DNA damage recognition proteins, transcription factors, mismatch repair proteins, and DNA polymerases discriminate between CP- and OX-GG DNA adducts, which could partly account for differences in the efficacy, toxicity, and mutagenicity of CP and OX. In addition, differential recognition of CP- and OX-GG adducts is highly dependent on the sequence context of the Pt-GG adduct. In particular, DNA binding protein domain HMGB1a binds to CP-GG DNA adducts with up to 53-fold greater affinity than to OX-GG adducts in the TGGA sequence context but shows much smaller differences in binding in the AGGC or TGGT sequence contexts. Here, simulations of the HMGB1a-Pt-DNA complex in the three sequence contexts revealed a higher number of interface contacts for the CP-DNA complex in the TGGA sequence context than in the OX-DNA complex. However, the number of interface contacts was similar in the TGGT and AGGC sequence contexts. The higher number of interface contacts in the CP-TGGA sequence context corresponded to a larger roll of the Pt-GG base pair step. Furthermore, geometric analysis of stacking of phenylalanine 37 in HMGB1a (Phe37) with the platinated guanines revealed more favorable stacking modes correlated with a larger roll of the Pt-GG base pair step in the TGGA sequence context. These data are consistent with our previous molecular dynamics simulations showing that the CP-TGGA complex was able to sample larger roll angles than the OX-TGGA complex or either CP- or OX-DNA complexes in the AGGC or TGGT sequences. We infer that the high binding affinity of HMGB1a for CP-TGGA is due to the greater flexibility of CP-TGGA compared to OX-TGGA and other Pt-DNA adducts. This increased flexibility is reflected in the ability of CP-TGGA to sample larger roll angles, which allows for a higher number of interface contacts between the Pt-DNA adduct and HMGB1a.

Original languageEnglish (US)
Pages (from-to)7608-7617
Number of pages10
JournalBiochemistry
Volume51
Issue number38
DOIs
StatePublished - Sep 25 2012

Fingerprint

oxaliplatin
DNA Adducts
Platinum
Cisplatin
DNA
Guanine
Base Pairing
DNA Mismatch Repair

All Science Journal Classification (ASJC) codes

  • Biochemistry

Cite this

Ramachandran, S., Temple, B., Alexandrova, A. N., Chaney, S. G., & Dokholyan, N. (2012). Recognition of platinum-DNA adducts by HMGB1a. Biochemistry, 51(38), 7608-7617. https://doi.org/10.1021/bi3008577
Ramachandran, Srinivas ; Temple, Brenda ; Alexandrova, Anastassia N. ; Chaney, Stephen G. ; Dokholyan, Nikolay. / Recognition of platinum-DNA adducts by HMGB1a. In: Biochemistry. 2012 ; Vol. 51, No. 38. pp. 7608-7617.
@article{b79c8bdc17954ee6b84bc1dc0878bedd,
title = "Recognition of platinum-DNA adducts by HMGB1a",
abstract = "Cisplatin (CP) and oxaliplatin (OX), platinum-based drugs used widely in chemotherapy, form adducts on intrastrand guanines (5′GG) in genomic DNA. DNA damage recognition proteins, transcription factors, mismatch repair proteins, and DNA polymerases discriminate between CP- and OX-GG DNA adducts, which could partly account for differences in the efficacy, toxicity, and mutagenicity of CP and OX. In addition, differential recognition of CP- and OX-GG adducts is highly dependent on the sequence context of the Pt-GG adduct. In particular, DNA binding protein domain HMGB1a binds to CP-GG DNA adducts with up to 53-fold greater affinity than to OX-GG adducts in the TGGA sequence context but shows much smaller differences in binding in the AGGC or TGGT sequence contexts. Here, simulations of the HMGB1a-Pt-DNA complex in the three sequence contexts revealed a higher number of interface contacts for the CP-DNA complex in the TGGA sequence context than in the OX-DNA complex. However, the number of interface contacts was similar in the TGGT and AGGC sequence contexts. The higher number of interface contacts in the CP-TGGA sequence context corresponded to a larger roll of the Pt-GG base pair step. Furthermore, geometric analysis of stacking of phenylalanine 37 in HMGB1a (Phe37) with the platinated guanines revealed more favorable stacking modes correlated with a larger roll of the Pt-GG base pair step in the TGGA sequence context. These data are consistent with our previous molecular dynamics simulations showing that the CP-TGGA complex was able to sample larger roll angles than the OX-TGGA complex or either CP- or OX-DNA complexes in the AGGC or TGGT sequences. We infer that the high binding affinity of HMGB1a for CP-TGGA is due to the greater flexibility of CP-TGGA compared to OX-TGGA and other Pt-DNA adducts. This increased flexibility is reflected in the ability of CP-TGGA to sample larger roll angles, which allows for a higher number of interface contacts between the Pt-DNA adduct and HMGB1a.",
author = "Srinivas Ramachandran and Brenda Temple and Alexandrova, {Anastassia N.} and Chaney, {Stephen G.} and Nikolay Dokholyan",
year = "2012",
month = "9",
day = "25",
doi = "10.1021/bi3008577",
language = "English (US)",
volume = "51",
pages = "7608--7617",
journal = "Biochemistry",
issn = "0006-2960",
publisher = "American Chemical Society",
number = "38",

}

Ramachandran, S, Temple, B, Alexandrova, AN, Chaney, SG & Dokholyan, N 2012, 'Recognition of platinum-DNA adducts by HMGB1a', Biochemistry, vol. 51, no. 38, pp. 7608-7617. https://doi.org/10.1021/bi3008577

Recognition of platinum-DNA adducts by HMGB1a. / Ramachandran, Srinivas; Temple, Brenda; Alexandrova, Anastassia N.; Chaney, Stephen G.; Dokholyan, Nikolay.

In: Biochemistry, Vol. 51, No. 38, 25.09.2012, p. 7608-7617.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Recognition of platinum-DNA adducts by HMGB1a

AU - Ramachandran, Srinivas

AU - Temple, Brenda

AU - Alexandrova, Anastassia N.

AU - Chaney, Stephen G.

AU - Dokholyan, Nikolay

PY - 2012/9/25

Y1 - 2012/9/25

N2 - Cisplatin (CP) and oxaliplatin (OX), platinum-based drugs used widely in chemotherapy, form adducts on intrastrand guanines (5′GG) in genomic DNA. DNA damage recognition proteins, transcription factors, mismatch repair proteins, and DNA polymerases discriminate between CP- and OX-GG DNA adducts, which could partly account for differences in the efficacy, toxicity, and mutagenicity of CP and OX. In addition, differential recognition of CP- and OX-GG adducts is highly dependent on the sequence context of the Pt-GG adduct. In particular, DNA binding protein domain HMGB1a binds to CP-GG DNA adducts with up to 53-fold greater affinity than to OX-GG adducts in the TGGA sequence context but shows much smaller differences in binding in the AGGC or TGGT sequence contexts. Here, simulations of the HMGB1a-Pt-DNA complex in the three sequence contexts revealed a higher number of interface contacts for the CP-DNA complex in the TGGA sequence context than in the OX-DNA complex. However, the number of interface contacts was similar in the TGGT and AGGC sequence contexts. The higher number of interface contacts in the CP-TGGA sequence context corresponded to a larger roll of the Pt-GG base pair step. Furthermore, geometric analysis of stacking of phenylalanine 37 in HMGB1a (Phe37) with the platinated guanines revealed more favorable stacking modes correlated with a larger roll of the Pt-GG base pair step in the TGGA sequence context. These data are consistent with our previous molecular dynamics simulations showing that the CP-TGGA complex was able to sample larger roll angles than the OX-TGGA complex or either CP- or OX-DNA complexes in the AGGC or TGGT sequences. We infer that the high binding affinity of HMGB1a for CP-TGGA is due to the greater flexibility of CP-TGGA compared to OX-TGGA and other Pt-DNA adducts. This increased flexibility is reflected in the ability of CP-TGGA to sample larger roll angles, which allows for a higher number of interface contacts between the Pt-DNA adduct and HMGB1a.

AB - Cisplatin (CP) and oxaliplatin (OX), platinum-based drugs used widely in chemotherapy, form adducts on intrastrand guanines (5′GG) in genomic DNA. DNA damage recognition proteins, transcription factors, mismatch repair proteins, and DNA polymerases discriminate between CP- and OX-GG DNA adducts, which could partly account for differences in the efficacy, toxicity, and mutagenicity of CP and OX. In addition, differential recognition of CP- and OX-GG adducts is highly dependent on the sequence context of the Pt-GG adduct. In particular, DNA binding protein domain HMGB1a binds to CP-GG DNA adducts with up to 53-fold greater affinity than to OX-GG adducts in the TGGA sequence context but shows much smaller differences in binding in the AGGC or TGGT sequence contexts. Here, simulations of the HMGB1a-Pt-DNA complex in the three sequence contexts revealed a higher number of interface contacts for the CP-DNA complex in the TGGA sequence context than in the OX-DNA complex. However, the number of interface contacts was similar in the TGGT and AGGC sequence contexts. The higher number of interface contacts in the CP-TGGA sequence context corresponded to a larger roll of the Pt-GG base pair step. Furthermore, geometric analysis of stacking of phenylalanine 37 in HMGB1a (Phe37) with the platinated guanines revealed more favorable stacking modes correlated with a larger roll of the Pt-GG base pair step in the TGGA sequence context. These data are consistent with our previous molecular dynamics simulations showing that the CP-TGGA complex was able to sample larger roll angles than the OX-TGGA complex or either CP- or OX-DNA complexes in the AGGC or TGGT sequences. We infer that the high binding affinity of HMGB1a for CP-TGGA is due to the greater flexibility of CP-TGGA compared to OX-TGGA and other Pt-DNA adducts. This increased flexibility is reflected in the ability of CP-TGGA to sample larger roll angles, which allows for a higher number of interface contacts between the Pt-DNA adduct and HMGB1a.

UR - http://www.scopus.com/inward/record.url?scp=84866689917&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866689917&partnerID=8YFLogxK

U2 - 10.1021/bi3008577

DO - 10.1021/bi3008577

M3 - Article

VL - 51

SP - 7608

EP - 7617

JO - Biochemistry

JF - Biochemistry

SN - 0006-2960

IS - 38

ER -

Ramachandran S, Temple B, Alexandrova AN, Chaney SG, Dokholyan N. Recognition of platinum-DNA adducts by HMGB1a. Biochemistry. 2012 Sep 25;51(38):7608-7617. https://doi.org/10.1021/bi3008577