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Amino Acid Asp181 of 5′-Flap Endonuclease 1 Is a Useful Target for Chemotherapeutic Development
- Source :
- Biochemistry. 48:9952-9958
- Publication Year :
- 2009
- Publisher :
- American Chemical Society (ACS), 2009.
-
Abstract
- DNA alkylation-induced damage is one of the most efficacious anti-cancer therapeutic strategies. Increased DNA alkylation and decreased DNA repair capacity in cancer cells is responsible for the effectiveness of DNA-alkylating therapies. 5’-Flap endonuclease 1 (Fen1) is an important enzyme involved in base excision repair (BER), specifically in long-patch (LP)-BER. Using the site-directed mutagenesis approach, we have identified an important role for amino acid Asp181 of Fen1 in its endonuclease activity. The Asp181 is thought be involved in Mg 2+ binding in the active site. Using structure-based molecular docking of Fen1 targeted to its metal-binding pocket M2 (Mg 2+ site), we have identified a potent small molecular weight inhibitor (SMI; NSC-281680) that efficiently blocks the LP-BER. In this study, we have demonstrated that the interaction of this SMI with Fen1 blocked its endonuclease activity, thereby blocking the LP-BER and enhancing the cytotoxic effect of DNAalkylating agent, Temozolomide (TMZ) in mismatch repair (MMR)-deficient and MMR-proficient colon cancer cells. The results further suggest that blockade of LP-BER by NSC-281680 may bypass other drug resistance mechanisms such as mismatch repair (MMR) defects. Therefore, our findings provide groundwork for the development of highly specific and safer structure-based small molecular inhibitors targeting the BER pathway, which can be used along with existing chemotherapeutic agents, like TMZ, as combination therapy for the treatment of colorectal cancer.
- Subjects :
- Models, Molecular
Aspartic Acid
DNA Repair
biology
Flap Endonucleases
DNA repair
Mutagenesis
Flap structure-specific endonuclease 1
Base excision repair
Biochemistry
Molecular biology
Article
Structure-Activity Relationship
Endonuclease
Cancer cell
biology.protein
Cancer research
Humans
DNA mismatch repair
Enzyme Inhibitors
Flap endonuclease
Colorectal Neoplasms
Subjects
Details
- ISSN :
- 15204995 and 00062960
- Volume :
- 48
- Database :
- OpenAIRE
- Journal :
- Biochemistry
- Accession number :
- edsair.doi.dedup.....90d075e3dcac22de9a7c4d3e9847227a