Ubiquitin ligases: guardians of mammalian development

Abstract

Mammalian development demands precision. Millions of molecules must be properly located in temporal order, and their function regulated, to orchestrate important steps in cell cycle progression, apoptosis, migration and differentiation, to shape developing embryos. Ubiquitin and its associated enzymes act as cellular guardians to ensure precise spatio-temporal control of key molecules during each of these important cellular processes. Loss of precision results in numerous examples of embryological disorders or even cancer. This Review discusses the crucial roles of E3 ubiquitin ligases during key steps of early mammalian development, their roles in human disease, and considers how new methods to manipulate and exploit the ubiquitin regulatory machineryfor example the development of molecular glues and PROTACsmight facilitate clinical therapy.

DNA Damage Induction Alters the Expression of Ubiquitin and SUMO Regulators in Preimplantation Stage Pig Embryos

“…Normal embryo development requires post-translational modifications of proteins including ubiquitylation and SUMOylation. These modifications are involved in the regulation of many developmental events such as chromatin remodeling, acquisition of cell totipotency, cell cleavage, embryo genome activation, transcription, and cell differentiation, as well as DNA repair and genome stability [ 13 , 19 ]. Ubiquitylation and SUMOylation are controlled by many proteins, but the expression of the genes encoding these proteins and their functions in the regulation of early embryo development of different species remain to be determined, particularly in the context of DDR.…”

“…Several hundred genes involved in the regulation of ubiquitylation/deubiquitylation and SUMOylation/deSUMOylation have been identified as participating in the modulation of different cell processes [ 13 ], including DDR [ 18 ]. Several of these genes were shown to be expressed in embryos [ 19 ] and to participate in the modulation of developmental events such as EGA [ 20 , 21 ], DNA methylation [ 22 ], and cell pluripotency [ 23 ]. However, the importance of many regulators of ubiquitylation/deubiquitylation and SUMOylation/deSUMOylation for normal embryo development remains to be studied.…”

Emerging Roles of Non-proteolytic Ubiquitination in Tumorigenesis

“…Also, the discovered deubiquitinase inhibitors related to tumor treatment are mainly concentrated in the USP family, and the relationship between the inhibitors of non-USP family members and the treatment of malignant tumors needs to be further studied ( Zhang et al, 2022 ). Interestingly, the innovative approaches of proteolysis targeting chimeras (PROTACs) and molecular glues might facilitate clinical cancer therapy ( Cruz Walma et al, 2022 ; Kung and Weber, 2022 ; Zhou and Xu, 2022 ). Consequently, it is essential further to investigate the role of ubiquitination enzymes in tumorigenesis.…”

Role of circRNA in E3 Modification under Human Disease

“…Moreover, the ubiquitin pathway is involved in the regulation of many basic cellular processes [ 56 , 57 ], including cell division and differentiation, immune response, autophagy, DNA repair, and apoptosis [ 48 ]. The processes of ubiquitination are separated into three basic steps, catalyzed by ubiquitin activating enzyme (E1), ubiquitin conjugating enzyme (E2) and ubiquitin ligase (E3) [ 58 , 59 ]. Polyubiquitination refers to the attachment of more than two Ub molecules to the same lysine residue of the substrate in a chain.…”