USP7 Is a Master Regulator of Genome Stability

Abstract

Genetic alterations, including DNA mutations and chromosomal abnormalities, are primary drivers of tumor formation and cancer progression. These alterations can endow cells with a selective growth advantage, enabling cancers to evade cell death, proliferation limits, and immune checkpoints, to metastasize throughout the body. Genetic alterations occur due to failures of the genome stability pathways. In many cancers, the rate of alteration is further accelerated by the deregulation of these processes. The deubiquitinating enzyme ubiquitin specific protease 7 (USP7) has recently emerged as a key regulator of ubiquitination in the genome stability pathways. USP7 is also deregulated in many cancer types, where deviances in USP7 protein levels are correlated with cancer progression. In this work, we review the increasingly evident role of USP7 in maintaining genome stability, the links between USP7 deregulation and cancer progression, as well as the rationale of targeting USP7 in cancer therapy.

A Proteomic Approach for Systematic Mapping of Substrates of Human Deubiquitinating Enzymes

“…One of those is PCNA, which is involved in the USP1 dependent DNA repair process [ 36 ]. TTK protein kinase that is associated with cell proliferation [ 37 ], a process that has been reported to be regulated by USP7 [ 38 ]. RNF10 E3 ligase whose rat homolog is important for myelin formation [ 39 ], thus possibly contributing to the neuronal pathogenesis caused by USP9X mutations [ 40 ].…”

Transcription Factors, R-Loops and Deubiquitinating Enzymes: Emerging Targets in Myelodysplastic Syndromes and Acute Myeloid Leukemia

“…As to the current view, USP7 inhibition destabilizes MDM2, the main E3 ligase targeting p53 for degradation, leading to p53 stabilization and p53-dependent tumor growth suppression [289,290]. Besides its action on p53, USP7 is largely involved in various cellular pathways, including genome stability maintenance, immune responses, epigenetic regulation, and HSC maintenance [291]. Within genome maintenance processes, USP7 acts as a master regulator of the response to DSBs through stabilization of the core components of DDR signaling, including the apical MRN-MDC1 complex, thereby impacting on both the NHEJ and HR DSB repair pathways [291,292].…”

“…Besides its action on p53, USP7 is largely involved in various cellular pathways, including genome stability maintenance, immune responses, epigenetic regulation, and HSC maintenance [291]. Within genome maintenance processes, USP7 acts as a master regulator of the response to DSBs through stabilization of the core components of DDR signaling, including the apical MRN-MDC1 complex, thereby impacting on both the NHEJ and HR DSB repair pathways [291,292]. Because of the important cellular roles of USP7, recent efforts focused on development of selective USP7 inhibitors as anticancer agents leading to the identification of several small molecules that are currently under preclinical testing [293].…”

Restraining CDK1–cyclin B activation: PP2A on the cUSP(7)

“…USP7 also regulates mitotic entry by stabilizing PLK1, another kinase which is highly active in the M phase and ensures proper alignment of chromatids prior to segregation. Notably, USP7 inhibitors have become an attractive cancer therapeutic strategy based on their ability to trigger degradation of MDM2, and thereby stabilize p53 (Valles et al, 2020). However, there is growing evidence of USP7 inhibitor‐related toxicity that is not mediated through p53 (Lecona et al, 2016; Agathanggelou et al, 2017), indicating that USP7 inhibitors impact other cellular processes.…”