In a view to develop new DNA alkylating antitumour drugs, evaluating the precise mechanism of action and the molecular/cellular consequences of the alkylation is a point of major interest. The benzo-b-acronycine derivative S23906-1 alkylates guanine nucleobases in the minor groove of the DNA helix and presents an original ability to locally open the double helix of DNA, which appears to be associated with its cytotoxic activity. However, the molecular mechanism linking adduct formation to cellular consequences is not precisely known. The objective of the present study was to identify proteins involved in the recognition and mechanism of action of S23906–DNA adducts. We found that GAPDH (glyceraldehyde-3-phosphate dehydrogenase) is a protein that binds to S23906-alkylated single-stranded, double-stranded and telomeric sequences in a drug-dependent and DNA sequence/structure-dependent manner. We used the CASTing (cyclic amplification of sequence targeting) method to identify GAPDH DNA-binding selectivity and then evaluated its binding to such selected S23906-alkylated sequences. At the cellular level, alkylation of S23906-1 results in an increase in the binding of GAPDH and its protein partner HMG (high-mobility group) B1 to the chromatin. Regarding the multiple roles of GAPDH in apoptosis and DNA repair, the cytotoxic and apoptotic activities of GAPDH were evaluated and present opposite effects in two different cellular models.
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Research Article|
April 25 2013
Protein recognition of the S23906-1–DNA adduct by nuclear proteins: direct involvement of glyceraldehyde-3-phosphate dehydrogenase (GAPDH)1
Gaëlle Lenglet;
Gaëlle Lenglet
1INSERM U837-JPARC, Team 4, IRCL, Place de Verdun, Lille 59045, France and IFR114-IMPRT, Lille 59000, France
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Sabine Depauw;
Sabine Depauw
1INSERM U837-JPARC, Team 4, IRCL, Place de Verdun, Lille 59045, France and IFR114-IMPRT, Lille 59000, France
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Denise Mendy;
Denise Mendy
1INSERM U837-JPARC, Team 4, IRCL, Place de Verdun, Lille 59045, France and IFR114-IMPRT, Lille 59000, France
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Marie-Hélène David-Cordonnier
Marie-Hélène David-Cordonnier
2
1INSERM U837-JPARC, Team 4, IRCL, Place de Verdun, Lille 59045, France and IFR114-IMPRT, Lille 59000, France
2To whom correspondence should be addressed (email marie-helene.david@inserm.fr).
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Publisher: Portland Press Ltd
Received:
June 26 2012
Revision Received:
January 02 2013
Accepted:
February 14 2013
Accepted Manuscript online:
February 14 2013
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2013 Biochemical Society
2013
Biochem J (2013) 452 (1): 147–159.
Article history
Received:
June 26 2012
Revision Received:
January 02 2013
Accepted:
February 14 2013
Accepted Manuscript online:
February 14 2013
Citation
Gaëlle Lenglet, Sabine Depauw, Denise Mendy, Marie-Hélène David-Cordonnier; Protein recognition of the S23906-1–DNA adduct by nuclear proteins: direct involvement of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Biochem J 15 May 2013; 452 (1): 147–159. doi: https://doi.org/10.1042/BJ20120860
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