NAIST 奈良先端科学技術大学院大学 バイオサイエンス領域


Double strand breaks form in DNA when alkylation repair intermediates collide

演題 Double strand breaks form in DNA when alkylation repair intermediates collide
講演者 Dr. Robert P. Fuchs(bioHalosis, CEO)
使用言語 English
日時 2024年3月21日(木曜日) 14:00~15:00
場所 Large Seminar Room (C109)

 The cellular response to alkylation damage is complex, involving multiple DNA repair and checkpoint pathways, depending on the DNA lesion, the cell type, and the cellular proliferation state. The repair of O-alkylation damage such as O6-methylguaine DNA adducts (O6-mG), is primarily mediated by direct reversal by MGMT (O6-methylguanine-DNA methyltransferase). Alternatively if left un-repaired, O6-mG lesions are converted into O6-mG:T mis-pairs during replication. These mis-pairs are substrates for the DNA mismatch repair pathway and as suggested, 30 years ago, repeated cycles of action of MMR may result in DNA double-strand breaks (futile-cycling model).
 However, using a novel DNA pull-down approach (IDAP a proprietary methodology of bioHalosis), we have demonstrated that DSBs may also result from the fortuitous encounter between a MMR-induced repair intermediate (initiated at O6-mG:C sites) and a BER-induced nick at an N-alkylation adducts located in close proximity in the opposite strand1. We refer to this model as the Repair Accident model2 which differs from the futile-cycling model as it does not involve replication. In the present talk, we will discuss potential strategies to improve the clinical use of TMZ based on the Repair Accident model.
 Our DNA pull-down methodology3, IDAP (Isolation of DNA-Associated Proteins) exhibits a broad range of applications. We will briefly present ongoing work where IDAP is applied to various research areas such as Tri Nucleotide Repeat (TNR) expansions, G4/i-motifs, epigenetic marks, transcriptional regulatory sequences…

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