UCHL3: a crucial deubiquitinase in DNA damage repair and tumor progression

Abstract

Ubiquitin carboxyl terminal hydrolase L3 (UCHL3) is a deubiquitinase belonging to UCH protease family. Previous studies have demonstrated that abnormal expression of UCHL3 is correlated with the development of human diseases, especially in tumors. Notably, UCHL3 exhibits contradictory biological functions across different cancer types. Initial studies identified UCHL3 as a tumor suppressor in prostate cancer. However, emerging evidence suggests that UCHL3 serves as an oncogene in other cancers. Several UCHL3 inhibitors have shown a promising anti-tumor effect in vitro and in vivo. UCHL3 has also been linked to DNA damage repair, which is essential for genome stability. Overexpression of UCHL3 enhances DNA damage repair induced resistance to chemotherapy or radiotherapy in certain tumor types. This review aims to summarize the promoting role of UCHL3 in DNA damage repair and its dual, paradoxical roles in tumor progression, along with the associated mechanisms, and to provide insights into the use of UCHL3 as a therapeutic target for overcoming DNA damage repair-mediated resistance to chemotherapy and radiotherapy, as well as for treating tumors.

Keywords: Chemoresistance; DNA damage repair; DNA damage response; Deubiquitinase; Radioresistance; Tumor progression; UHCL3.

Fig. 1

The crystal structure of UCHL3. RCSB Protein Data Bank ( https://www.rcsb.org/) is used to obtain the crystal structure UCHL3. UCHL3 is a bilobed structure consisting of a six-stranded antiparallel β-sheet in the center and α-helices packing on either side

Fig. 2

The role and the underlying mechanisms of UCHL3 in DNA damage repair. UCHL3 plays an important role in DSB and DPC repair. When DSB occurs, UCHL3 deubiquitinates RAD51 or Ku80 to facilitate HR or NHEJ, respectively, thus promoting DNA damage repair. UCHL3 also deubiquitinates TDP1 to accelerate the removing of the TOP1 adduct that links it to DNA, which in turn repair Top1cc induced DPC

Fig. 3

The role and the underlying mechanisms of UCHL3 in tumor progression. UCHL3 acts as a tumor promoter in most tumors except for prostate cancer. UCHL3 exerts its tumor promoting role mainly through deubiquitinating substrates including GNG12, BRD4, FOXM1, AHR, LSH, Vimentin, β-catenin, MTA2, YAP, NRF2, TRAF2 and NEDD8, leading to the accumulation of these crucial oncoprotein and the subsequent tumor development. Meanwhile, UCHL3 also activates the PI3K/AKT/SOX2 signaling to promote CRC onset. In PCa, the tumor suppressing role of UCHL3 is achieved by inactivating PI3K/AKT and EMT signaling

Fig. 4

Positive feedback loop of UCHL3 in ATC. UCHL3 deubiquitinates and stabilizes YAP. The increased YAP forms a transcriptional complex with TEAD4, further activating UCHL3 transcription, thereby establishing a positive feedback loop that continuously amplifies the oncogenic activities of UCHL3

Fig. 5

The regulation of UCHL3 expression and deubiquitinating activity. UCHL3 can be regulated by transcription factors, ncRNAs, DDR signaling and farrerol. Transcription factor C-Fos and TEAD4 binds to the promoter region of UCHL3 and thus promotes UCHL3 transcription expression. LINC00665 sponges miR-582-5p to up-regulate UCHL3 expression. LncRNA GIAT4RA and CircMTA2 attenuates or facilitates the deubiquitinating activity of UCHL3 on substrate via interacting with substrate or UCHL3, respectively. During DNA damage, ATM phosphorylates UCHL3 to either increase deubiquitinating activity or promote its degradation in HR or NHEJ. Farrerol binds to R215 and K187 of UCHL3 to stimulate the deubiquitinating activity of UCHL3