Abstract
DNA alkylating drugs have been used in clinics for more than seventy years. The diversity of their mechanism of action (major/minor groove; mono-/bis-alkylation; intra-/inter-strand crosslinks; DNA stabilization/destabilization, etc.) has undoubtedly major consequences on the cellular response to treatment. The aim of this review is to highlight the variety of established protein recognition of DNA adducts to then particularly focus on glyceraldehyde-3-phosphate dehydrogenase (GAPDH) function in DNA adduct interaction with illustration using original experiments performed with S23906-1/DNA adduct. The introduction of this review is a state of the art of protein/DNA adducts recognition, depending on the major or minor groove orientation of the DNA bonding as well as on the molecular consequences in terms of double-stranded DNA maintenance. It reviews the implication of proteins from both DNA repair, transcription, replication and chromatin maintenance in selective DNA adduct recognition. The main section of the manuscript is focusing on the implication of the moonlighting protein GAPDH in DNA adduct recognition with the model of the peculiar DNA minor groove alkylating and destabilizing drug S23906-1. The mechanism of action of S23906-1 alkylating drug and the large variety of GAPDH cellular functions are presented prior to focus on GAPDH direct binding to S23906-1 adducts.
Highlights
The concept of chemotherapy to treat cancer was born with the experiments of the famous chemist Prof P
The aim of the present study is first to give an overview on protein/DNA adduct recognition as an introduction to focus on the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) cellular functions and its particular role on protein recognition of DNA damage and its recently discovered implication in DNA repair
As presented in the previous section, GAPDH, High Mobility Group (HMG)-B1, HSC70, and PDIA3/ERp57 proteins are implicated in a complex as a MutS-independent MMR repair machinery [193,194] and could be implicated in S23906-1/DNA adducts repair in the p53-mutated cell line (Figure 4)
Summary
The concept of chemotherapy to treat cancer was born with the experiments of the famous chemist Prof P. The first synthesized alkylating agent was bis-(β-chloroethyl)-sulfide in the mid-nineteenth century as a precursor of other sulfur mustards Those sulfur mustards are considered the first anti-cancer agents from the initial observation of the leukopenic effect (decrease of lymph nodes and bone marrow cell number) in soldiers that were exposed to mustard gas during World War I and further accidentally exposed troops after the explosion of military stocks of mustard gas in December 1943. Results showed interesting antitumor activity but the primary promising reduction of nodes was rapidly followed by relapse associated with chemoresistance (reviewed in [2]) Since this pioneer period, mustards are still used in cancer treatment (chlorambucil, melphalan) but anti-cancer chemotherapy was, thankfully, largely extended to better target cancer cells with a much wider pharmacopeia including a large variety of drugs from several families of alkylating agents and by new strategies of targeted therapies. This latter part is illustrated with the particular example of the S23906-1 DNA adduct formed on either double- or single-stranded DNA or on telomeric DNAs and its recognition by GAPDH
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
