Increasing evidence links RNA methyltransferases to DNA damage repair. METTL16 is now shown to antagonize homologous recombination by preventing DNA-end resection via MRE11. Thus, METTL16 may represent a cancer vulnerability that can be used to identify patients able to benefit from combination therapies with DNA-damaging agents. DNA damage repair is an essential process in cell biology with significant implications for cancer. Chemotherapy induces the accumulation of DNA damage in the fast-proliferating cancer cells, leading to apoptosis when cells cannot fix this damage. Thus, understanding the basic mechanisms of DNA damage repair could allow the identification of new treatments with higher efficacy and fewer side effects. This is particularly relevant for cancers characterized by genome instability, such as pancreatic ductal adenocarcinoma (PDAC)1. PDAC has a poor prognosis, and chemotherapy has only a modest effect on it. In this issue of Nature Cancer, Zeng et al.2 identified an important role of the m~6A RNA methyltransferase METTL16 in preventing DNA damage repair by sequestering the double-strand break (DSB) repair protein MRE11, thereby making PDAC cells expressing elevated levels of METTL16 more susceptible to the combination of poly(ADP-ribose)polymerase (PARP inhibitors and chemotherapy. The combination of PARP1 inhibitors with DNA-damaging agents is currently being tested in patients with DNA-repair deficiencies such as BRCA1 or BRCA2 mutations~3-5. Therefore, identifying additional drug-sensitizing alterations, such as METTL16 upregulation, opens up new therapeutic possibilities.
Perez-Pepe M、Alarcón C.R
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Department of Pharmacology, Yale University School of Medicine, New Haven, CT, United States
NSTL
