Ubiquitin-fold modifier 1 (UFM1) is a newly identified ubiquitin-like protein that has been conserved during the evolution of multicellular organisms. In a similar manner to ubiquitin, UFM1 can become covalently linked to the lysine residue of a substrate via a dedicated enzymatic cascade. Although a limited number of substrates have been identified so far, UFM1 modification (UFMylation) has been demonstrated to play a vital role in a variety of cellular activities, including mammalian development, ribosome biogenesis, the DNA damage response, endoplasmic reticulum stress responses, immune responses, and tumorigenesis. In this review, we summarize what is known about the UFM1 enzymatic cascade and its biological functions, and discuss its recently identified substrates. We also explore the pathological role of UFMylation in human disease and the corresponding potential therapeutic targets and strategies.

Genomic DNA damage occurs as an inevitable consequence of exposure to harmful exogenous and endogenous agents. Therefore, the effective sensing and repair of DNA damage are essential for maintaining genomic stability and cellular homeostasis. Inappropriate responses to DNA damage can lead to genomic instability and, ultimately, cancer. Protein post-translational modifications (PTMs) are a key regulator of the DNA damage response (DDR), and recent progress in mass spectrometry analysis methods has revealed that a wide range of metabolites can serve as donors for PTMs. In this review, we will summarize how the DDR is regulated by lipid metabolite-associated PTMs, including acetylation, S-succinylation, N-myristoylation, palmitoylation, and crotonylation, and the implications for tumorigenesis. We will also discuss potential novel targets for anti-cancer drug development.