Lack of mismatch repair enhances resistance to methylating agents for cells deficient in oxidative demethylation.

Autor: Gutierrez R; Department of Cancer Biology, Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute at the City of Hope, Duarte, California, USA., Chan AYS; Department of Cancer Biology, Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute at the City of Hope, Duarte, California, USA., Lai SWT; Department of Diabetes and Cancer Metabolism, Beckman Research Institute at the City of Hope, Duarte, California, USA., Itoh S; Department of Cancer Biology, Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute at the City of Hope, Duarte, California, USA., Lee DH; Department of Biological Sciences, College of Natural Sciences, Chonnam National University, Gwangju, South Korea., Sun K; Department of Diabetes and Cancer Metabolism, Beckman Research Institute at the City of Hope, Duarte, California, USA., Battad A; Department of Diabetes and Cancer Metabolism, Beckman Research Institute at the City of Hope, Duarte, California, USA., Chen S; Department of Cancer Biology, Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute at the City of Hope, Duarte, California, USA., O'Connor TR; Department of Cancer Biology, Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute at the City of Hope, Duarte, California, USA. Electronic address: toconnor@coh.org., Shuck SC; Department of Diabetes and Cancer Metabolism, Beckman Research Institute at the City of Hope, Duarte, California, USA. Electronic address: sshuck@coh.org.
Jazyk: angličtina
Zdroj: The Journal of biological chemistry [J Biol Chem] 2024 Aug; Vol. 300 (8), pp. 107492. Date of Electronic Publication: 2024 Jun 24.
DOI: 10.1016/j.jbc.2024.107492
Abstrakt: The human alkylation B (AlkB) homologs, ALKBH2 and ALKBH3, respond to methylation damage to maintain genomic integrity and cellular viability. Both ALKBH2 and ALKBH3 are direct reversal repair enzymes that remove 1-methyladenine (1meA) and 3-methylcytosine (3meC) lesions commonly generated by alkylating chemotherapeutic agents. Thus, the existence of deficiencies in ALKBH proteins can be exploited in synergy with chemotherapy. In this study, we investigated possible interactions between ALKBH2 and ALKBH3 with other proteins that could alter damage response and discovered an interaction with the mismatch repair (MMR) system. To test whether the lack of active MMR impacts ALKBH2 and/or ALKBH3 response to methylating agents, we generated cells deficient in ALKBH2, ALKBH3, or both in addition to Mlh homolog 1 (MLH1), another MMR protein. We found that MLH1 ko ALKBH3 ko cells showed enhanced resistance toward S N 1- and S N 2-type methylating agents, whereas MLH1 ko ALKBH2 ko cells were only resistant to S N 1-type methylating agents. Concomitant loss of ALKBH2 and ALKBH3 (ALKBH2 ko 3 ko ) rendered cells sensitive to S N 1- and S N 2-agents, but the additional loss of MLH1 enhanced resistance to both types of damage. We also showed that ALKBH2 ko 3 ko cells have an ATR-dependent arrest at the G 2 /M checkpoint, increased apoptotic signaling, and replication fork stress in response to methylation. However, these responses were not observed with the loss of functional MLH1 in MLH1 ko ALKBH2 ko 3 ko cells. Finally, in MLH1 ko ALKBH2 ko 3 ko cells, we observed elevated mutant frequency in untreated and temozolomide treated cells. These results suggest that obtaining a more accurate prognosis of chemotherapeutic outcome requires information on the functionality of ALKBH2, ALKBH3, and MLH1.
Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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