MRE11 UFMylation promotes ATM activation

TLDR

DNA double‑strand breaks trigger a DNA damage response that relies on ATM activation by the MRN complex, yet the role of ubiquitin‑like modifier UFMylation in this pathway remains largely unknown. We show that UFMylation of MRE11 at K282 is essential for MRN complex assembly, optimal ATM activation, homologous recombination repair, and genome stability, and that a cancer‑associated MRE11(G285C) mutation phenocopies the UFMylation‑defective mutant, highlighting MRE11 UFMylation as a potential therapeutic target.

Abstract

A proper DNA damage response (DDR) is essential to maintain genome integrity and prevent tumorigenesis. DNA double-strand breaks (DSBs) are the most toxic DNA lesion and their repair is orchestrated by the ATM kinase. ATM is activated via the MRE11-RAD50-NBS1 (MRN) complex along with its autophosphorylation at S1981 and acetylation at K3106. Activated ATM rapidly phosphorylates a vast number of substrates in local chromatin, providing a scaffold for the assembly of higher-order complexes that can repair damaged DNA. While reversible ubiquitination has an important role in the DSB response, modification of the newly identified ubiquitin-like protein ubiquitin-fold modifier 1 and the function of UFMylation in the DDR is largely unknown. Here, we found that MRE11 is UFMylated on K282 and this UFMylation is required for the MRN complex formation under unperturbed conditions and DSB-induced optimal ATM activation, homologous recombination-mediated repair and genome integrity. A pathogenic mutation MRE11(G285C) identified in uterine endometrioid carcinoma exhibited a similar cellular phenotype as the UFMylation-defective mutant MRE11(K282R). Taken together, MRE11 UFMylation promotes ATM activation, DSB repair and genome stability, and potentially serves as a therapeutic target.