The Role of Base Excision Repair and Mismatch Repair Proteins in the Processing of Cisplatin Interstrand Cross-Links
Year: 2014
Type: article
Abstract: Cisplatin is a well-known anticancer agent that forms a part of many combination chemotherapeutic treatments used against a variety of human cancers.Despite successful treatment, the development of resistance is the major limitation of the cisplatin based therapy.Base excision repair modulates cisplatin cytotoxicity.Moreover, mismatch repair deficiency gives rise to cisplatin resistance and leads to poor prognosis of the disease.Various models have been proposed to explain this low level of resistance caused due to loss of MMR proteins.In our previous studies, we have shown that BER processing of the cisplatin ICLs is mutagenic.Our studies showed that these mismatches lead to the activation and the recruitment of mismatch repair proteins.The role of MMR proteins in the processing of cisplatin ICLs has not been studied before.Here, we show that MMR proteins are required to maintain cisplatin ICLs on the DNA leading to increased cellular sensitivity.We distinguished between the requirement of different downstream MMR proteins for maintaining cisplatin sensitivity.We also show that, MutSα heterocomplex is required to maintain cisplatin sensitivity whereas Mutsβ List of Abbreviations APE1……………………………………………... Apurinic/apyrimidinic endonuclease 1 CSA………………………………………………………………... cockayne syndrome A CSB………………………………………………………………... cockayne syndrome B DSB………………………………………………………………….. double-strand break EXO I……………………………………………………………………… Exonuclease I FA……………………………………………………………………….. Fanconi Anemia FEN1………………………………………………………………….flap endonuclease I HNPCC……………………………………… hereditary non-polyposis colorectal cancer HR…………………………………………………………… homologous recombination ICLs………………………………………………………………… Interstrand crosslinks IDLs……………………………………………………………….insertion deletion loops KD…………………………………………………………………………….. knockdown LP-BER…………………………………………………………………... long patch BER MBD4………………………………………………. methyl CPG domain binding protein MMC………………………………………………………………………… mitomycin C MMR……………………………………………………………………...Mismatch repair MLH1…………………………………………………………………… MutL homolog 1 MSH…………………………………………………………………… MutS homologues MSI……………………………………………………………… microsatellite instability Neil 1……………………………………………………….. Nei endonuclease VIII-like 1 NER…………………………………………………………… Nucleotide excision repair PARP1……………………………………………………… Poly ADP ribose polymerase PCNA…………………………………………………… proliferating cell nuclear antigen Polβ……………………………………………………………………….Polymerase beta RFC…………………………………………………………………… replication factor C ROS……………………………………………………………... Reactive oxygen species xiii RT……………………………………………………………………….room temperature SMUG1…………….……single-strand selective monofunctional uracil DNA glycosylase SSBs………………………………………………………………….. single-strand breaks ssDNA……………………………………………………………….single-stranded DNA TC-NER……………………………………………………….transcription coupled NER TDG………………………………………………... thymine/uracil mismatch glycosylase TFIIH…………………………………………………………….
Author: Akshada Sawant
Institution: University of Toledo
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2336586647