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Mechanistic insight into the repair of C8-linked pyrrolobenzodiazepine monomer-mediated DNA damage

Research output: Contribution to journalArticlepeer-review

Asha Mary Joseph, Kazi Nahar, Saheli Daw, Mahbub Hasan, Reebecca Lo, Tung Le, Miraz Rahman, Anjana Badrinarayanan

Original languageEnglish
Pages (from-to)1-13
Number of pages13
JournalRSC Medicinal Chemistry
Volume32
Issue number2
Early online date18 Oct 2022
DOIs
Accepted/In press18 Oct 2022
E-pub ahead of print18 Oct 2022

Bibliographical note

Funding Information: AMJ and AB thank members of the AB lab for feedback on the work. AMJ acknowledges support from DST SERB N-PDF. AB acknowledges support from the DBT-IYBA grant (BT/12/IYBA/2019/10) and intra-mural funding from NCBS-TIFR (1303/3/2019/R&D-II/DAE/4749). TBKL acknowledges support from the Royal Society University Research Fellowship Renewal (URF\R\201020) and BBSRC (BBS/E/J/000PR9791). KMR annd MMH acknowledge support from the Commonwealth Scholarship Commission in the UK (BDCS-2019-57). Publisher Copyright: © 2022 RSC.

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King's Authors

Abstract

Pyrrolobenzodiazepines (PBDs) are naturally occurring DNA binding compounds that possess anti-tumor and anti-bacterial activity. Chemical modifications of PBDs can result in improved DNA binding, sequence specificity and enhanced efficacy. More recently, synthetic PBD monomers have shown promise as payloads for antibody drug conjugates and anti-bacterial agents. The precise mechanism of action of these PBD monomers and their role in causing DNA damage remains to be elucidated. Here we characterized the damage-inducing potential of two C8-linked PBD bi-aryl monomers in Caulobacter crescentus and investigated the strategies employed by cells to repair the same. We show that these compounds cause DNA damage and efficiently kill bacteria, in a manner comparable to the extensively used DNA cross-linking agent mitomycin-C (MMC). However, in stark contrast to MMC which employs a mutagenic lesion tolerance pathway, we implicate essential functions for error-free mechanisms in repairing PBD monomer-mediated damage. We find that survival is severely compromised in cells lacking nucleotide excision repair and to a lesser extent, in cells with impaired recombination-based repair. Loss of nucleotide excision repair leads to significant increase in double-strand breaks, underscoring the critical role of this pathway in mediating repair of PBD-induced DNA lesions. Together, our study provides comprehensive insights into how mono-alkylating DNA-targeting therapeutic compounds like PBD monomers challenge cell growth, and identifies the specific mechanisms employed by the cell to counter the same.

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