期刊
NATURE CANCER
卷 3, 期 9, 页码 1088-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s43018-022-00429-3
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资金
- National Natural Science Foundation of China [81874184, 82072736, 32090032, 32070713, 82172994, 82002985]
- Key Research and Development Projects of Hubei Province [2021BCA116]
- Mayo Foundation
- China Scholar Council [201806160023]
- NIH [T32 GM65841]
This study reveals the potential role of METTL16 in the treatment of PDAC, particularly in cases with high METTL16 expression. Combining PARP inhibitors with gemcitabine may be an effective treatment strategy.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. Characterization of genetic alterations will improve our understanding and therapies for this disease. Here, we report that PDAC with elevated expression of METTL16, one of the 'writers' of RNA N-6-methyladenosine modification, may benefit from poly-(ADP-ribose)-polymerase inhibitor (PARPi) treatment. Mechanistically, METTL16 interacts with MRE11 through RNA and this interaction inhibits MRE11's exonuclease activity in a methyltransferase-independent manner, thereby repressing DNA end resection. Upon DNA damage, ATM phosphorylates METTL16 resulting in a conformational change and autoinhibition of its RNA binding. This dissociates the METTL16-RNA-MRE11 complex and releases inhibition of MRE11. Concordantly, PDAC cells with high METTL16 expression show increased sensitivity to PARPi, especially when combined with gemcitabine. Thus, our findings reveal a role for METTL16 in homologous recombination repair and suggest that a combination of PARPi with gemcitabine could be an effective treatment strategy for PDAC with elevated METTL16 expression. Lou and colleagues describe the role of METTL16 in homologous recombination repair and demonstrate that PARP inhibition may be beneficial in the treatment of PDAC that is characterized by high METTL16.
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