USP7 Is a Master Regulator of Genome Stability.

Gabrielle J Valles,Roger Woodgate,Irina Bezsonova,Nicholas W Ashton

doi:10.3389/fcell.2020.00717

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.

Highlights

Maintaining the genomic integrity of cells is vital, as alterations to the genetic code can result in deregulation of cellular function, malignant transformation or cell death
As SIRT1 was recently found to be deubiquitinated and stabilized by ubiquitin specific protease 7 (USP7), these findings suggest another way through which USP7 can regulate SUV39H1 activity and p53 transcription (Song et al, 2020)
mediator of DNA damage checkpoint 1 (MDC1) is a binding partner of the MRN nuclease complex (Goldberg et al, 2003) and functions in the initial detection and signaling of DSBs (Stewart et al, 2003). This is demonstrated by the failed recruitment of the downstream DNA repair proteins 53BP1 and BRCA1 in MDC1-depleted cells following DNA damage; this defect is mimicked in cells depleted of USP7 (Su et al, 2018)

Summary

INTRODUCTION

Maintaining the genomic integrity of cells is vital, as alterations to the genetic code can result in deregulation of cellular function, malignant transformation or cell death. The “switching loop,” a loop that is proximal to the active site, undergoes even larger rearrangement and becomes more structured upon ubiquitin-binding (Hu et al, 2001; Faesen et al, 2011a) The existence of these two distinct conformations assumed by the USP7 catalytic domain may be a mechanism employed by the enzyme to regulate its activity (Hu et al, 2001; Ozen et al, 2018). Despite the limitations above, stabilizing proteins by removal of proteasome-targeting K48 polyubiquitin chains is a common mechanism by which USP7 regulates many of its characterized substrates These USP7 substrates include a high number of E3 ubiquitin ligases and their target substrates (Kim and Sixma, 2017). We will consider roles of USP7 in the ‘last resort’ pathway of apoptosis

Cell Cycle Regulation

Telomere Maintenance

Nucleotide Excision Repair

DNA Damage Bypass

CONCLUSION

AUTHOR CONTRIBUTIONS