The Ubiquitin Proteasome Pathway (UPP) in the regulation of cell cycle control and DNA damage repair and its implication in tumorigenesis

Abstract

Accumulated evidence supports that the ubiquitin proteasome pathway (UPP) plays a crucial role in protein metabolism implicated in the regulation of many biological processes such as cell cycle control, DNA damage response, apoptosis, and so on. Therefore, alterations for the ubiquitin proteasome signaling or functional impairments for the ubiquitin proteasome components are involved in the etiology of many diseases, particularly in cancer development. In this minireview, we first give a brief outline for the ubiquitin proteasome pathway, we then discuss with focus for the ubiquitin proteasome pathway in the regulation of cell cycle control and DNA damage response, the relevance for the altered regulation of these signaling pathways in tumorigenesis is also reviewed. We finally assess and summarize the advancement for targeting the ubiquitin proteasome pathway in cancer therapy. A better understanding of the biological functions underlying ubiquitin regulatory mechanisms would provide us a wider prospective on cancer treatment.

Keywords: DNA damage response; Ubiquitin proteasome pathway; cell cycle; tumorigenesis; ubiquitination.

Figure 1

The ubiquitin proteasome pathway. Ubiquitin is activated by adding to E1, and E1 transfers ubiquitin to E2, E2 then interacts with E3, leading to the formation of a polyubiquitin chain. Finally, the targeted protein is degraded to small peptides by the 26S proteasome. E1: Ubiquitin activating enzyme; E2: Ubiquitin conjugating enzyme; E3: Ubiquitin ligases.

Figure 2

The ubiquitin ligase complexes SCF and APC/C in ubiquitin-mediated proteolysis of regulatory molecules essential for cell cycle control. Two major ubiquitin ligase complexes, SCF and APC/C, are responsible for the specific ubiquitination of cell cycle regulators through the proteasome targeted degradation. SCF ligase complexes control the G1 to S transition, while APC/C ligases mediate the onset and exit of mitosis.

Figure 3

A. A diagram shows the sequence domains and motifs in BRCA1. BRCA1 contains an N-terminal RING domain that possesses E3 ubiquitin ligase activity, and a C-terminal tandem BRCT domain that facilitates phosphoprotein binding. BRCA1 possesses 3 phosphorylation sites that initiate the signaling cascade by the ATM-dependent phosphorylation. BRCA1 has two nuclear localization signals (NLS) which import BRCA1 into the nucleus, while two nuclear export sequences (NES) within the RING domain are responsible for the export of BRCA1 from the nucleus into the cytoplasm. B. Signaling cascade for BRCA1-mediated DNA damage repair. In response to DNA damage, ATM phosphorylates BRCA1. Upon phosphorylation BRCA1 forms a heterodimer with BRAD1, which then recruits additional partners such as BRCA2 and Rad5. Upon the assembly of a complex with these partners, BRCA1 is then relocated into the DNA damage site, where it serves to promote high fidelity repair processes.