METTL16 antagonizes MRE11-mediated DNA end resection and confers synthetic lethality to PARP inhibition in pancreatic ductal adenocarcinoma

Nat Cancer. 2022 Sep;3(9):1088-1104. doi: 10.1038/s43018-022-00429-3. Epub 2022 Sep 22.

Abstract

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 N6-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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Diphosphate Ribose
  • Carcinoma, Pancreatic Ductal* / drug therapy
  • DNA
  • Exonucleases / genetics
  • Humans
  • MRE11 Homologue Protein* / genetics
  • Methyltransferases* / genetics
  • Pancreatic Neoplasms* / drug therapy
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Poly(ADP-ribose) Polymerases / genetics
  • RNA
  • Synthetic Lethal Mutations

Substances

  • MRE11 protein, human
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Adenosine Diphosphate Ribose
  • RNA
  • DNA
  • METTL16 protein, human
  • Methyltransferases
  • Poly(ADP-ribose) Polymerases
  • Exonucleases
  • MRE11 Homologue Protein

Supplementary concepts

  • Pancreatic Carcinoma