Basis for recognition of cisplatin-modified DNA by high-mobility-group proteins

Ohndorf, Uta-Maria; Rould, Mark A.; He, Qing; Pabo, Carl O.; Lippard, Stephen J.

doi:10.1038/21460

Cited by 562 publications

(767 citation statements)

References 28 publications

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“…B. Crystal structure [16] of HMGB1 (box A; red) bound to DNA (cyan) kinked by a chemical cross-link (yellow) with intercalation of F37 (green). C. Model for random and transient binding of HMGB proteins (red) to form an ensemble of DNA conformations with reduced end-to-end distance (blue arrows) enhancing of the rate of ligasecatalyzed DNA cyclization.…”

Section: Hmgb Mechanismsmentioning

confidence: 99%

Transient HMGB protein interactions with B-DNA duplexes and complexes

Zimmerman

Maher

2008

Biochemical and Biophysical Research Communications

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HMGB proteins are abundant, non-histone proteins in eukaryotic chromatin. HMGB proteins contain one or two conserved "HMG boxes" and can be sequence specific or nonspecific in their DNA binding. HMGB proteins cause strong DNA bending and bind preferentially to deformed DNAs. We wish to understand how HMGB proteins increase the apparent flexibility of non-distorted B-form DNA. We test the hypothesis that HMGB proteins bind transiently, creating an ensemble of distorted DNAs with rapidly-interconverting conformations. We show that binding of B-form DNA by HMGB proteins is both weak and transient under conditions where DNA cyclization is strongly enhanced. We also detect novel complexes in which HMGB proteins simultaneously bind more than one DNA duplex.Double-stranded DNA is among the least flexible biopolymers. The local stiffness of DNA is reflected in its persistence length, P, (~150 bp) [1]. The global flexibility of naked DNA in solution is insufficient to allow the degree of compaction required for packaging within cells, or for deformed structures involved in DNA replication, recombination, and transcriptional control. While some controversy exists concerning the accuracy of predictive models for DNA flexibility over short lengths [2;3;4], it is clear that short lengths of DNA require proteins to induce strongly bent and looped conformations.The apparent physical properties of DNA may differ in vitro and in vivo [5;6]. Activation over short distances in assays of eukaryotic transcription activation in vitro raised the possibility of apparent DNA flexibility enhancement by nuclear factors [7]. Indeed, heat-resistant HMGB proteins in nuclear extracts were found to dramatically enhance the cyclization of short DNA restriction fragments by DNA ligase [8].Eukaryotic HMGB proteins are abundant small non-histone chromosomal proteins [9;10;11; 12] that share one or two copies of an ~80-amino acid HMG box domain. Fig. 1A shows the amino acid alignment of HMG box domains, illustrating the partial conservation of intercalating residues [13]. As shown in Fig. 1B, this domain specifies three α-helices (red) whose L-shaped fold engages one face of DNA while delivering one or two intercalating residues into the minor groove [14;15;16]. Biophysical studies have provided some insights into the thermodynamic basis of DNA binding [17;18;19;20]. HMGB proteins to induce DNA kinking or bending of 22;23;24;25], and bind preferentially to distorted DNA structures [16;21;26]. HMGB proteins may stabilize DNA bending either by *To whom correspondence should be addressed at maher@mayo.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all l...

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Section: Hmgb Mechanismsmentioning

confidence: 99%

Transient HMGB protein interactions with B-DNA duplexes and complexes

Zimmerman

Maher

2008

Biochemical and Biophysical Research Communications

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“…Many subsequent studies by us and others have led to the characterization of the structures of the 1,3-cis-{Pt(NH 3 ) 2 } 2+ -d(GpTpG) intrastrand adduct formed by cisplatin and carboplatin, the 1,2-cis-{Pt(R, R-DACH)} 2+ -d(GpG) intrastrand adduct formed by oxaliplatin, the 1,2-cis-{Pt(NH 3 )(NH 2 C 6 H 11 )} 2+ -d(GpG) intrastrand adducts formed by satraplatin, and the cis-{Pt(NH 3 ) 2 } 2+ -d(GG) interstrand cross-link formed by cisplatin [20]. In addition, the structure of DNA bearing a 1,2-cis-{Pt(NH 3 ) 2 } 2+ -d(GpG) intrastrand cisplatin adduct complexed with the high mobility group box protein HMGB1 was solved [21] as was the structure of a platinated nucleosome core particle prepared from histone octamer proteins and double-stranded 146-mer DNA bearing the site-specific 1,3-cis-{Pt(NH 3 ) 2 } 2+ -d(GpTpG) cross-link [22].…”

Section: (B) Aquation/activationmentioning

confidence: 99%

Third row transition metals for the treatment of cancer

Johnstone

Suntharalingam

Lippard

2015

Phil. Trans. R. Soc. A.

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Platinum compounds are a mainstay of cancer chemotherapy, with over 50% of patients receiving platinum. But there is a great need for improvement. Major features of the cisplatin mechanism of action involve cancer cell entry, formation mainly of intrastrand cross-links that bend and unwind nuclear DNA, transcription inhibition and induction of cell-death programmes while evading repair. Recently, we discovered that platinum cross-link formation is not essential for activity. Monofunctional Pt compounds such as phenanthriplatin, which make only a single bond to DNA nucleobases, can be far more active and effective against a range of tumour types. Without a cross-link-induced bend, monofunctional complexes can be accommodated in the major groove of DNA. Their biological mechanism of action is similar to that of cisplatin. These discoveries opened the door to a large family of heavy metal-based drug candidates, including those of Os and Re, as will be described.

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“…In the next mechanistic step it is assumed that the Pt-GG adduct is recognized by proteins, followed by either stabilization of the distorted DNA structure or removal of the lesion through repair (35,66). Such Pt-GG chelates are basically the same (65) in many cases, and even when a protein is bound to it, this kinked DNA structure is retained (67). The biological consequences of the protein binding at GG-platinated sites are the next challenge to understand (68).…”

Section: The Recognition Of the Cisplatin Gg Adductmentioning

confidence: 99%