Abstract
Speckle-type BTB/POZ protein (SPOP) is a substrate recognition receptor of the cullin-3 (CUL3)/RING type ubiquitin E3 complex. To date, approximately 30 proteins have been identified as ubiquitinated substrates of the CUL3/SPOP complex. Pathologically, missense mutations in the substrate-binding domain of SPOP have been found in prostate and endometrial cancers. Prostate and endometrial cancer-associated SPOP mutations lose and increase substrate-binding ability, respectively. Expression of these SPOP mutants, thus, causes aberrant turnovers of the substrate proteins, leading to tumor formation. Although the molecular properties of SPOP and its cancer-associated mutants have been intensively elucidated, their cellular functions remain unclear. Recently, a number of studies have uncovered the critical role of SPOP and its mutants in DNA damage response and DNA replication. In this review article, we summarize the physiological functions of SPOP as a “gatekeeper” of genome stability.
Highlights
Ubiquitination is a post-translational modification that results in the addition of ubiquitin molecules to a protein in eukaryotes
These data suggest that androgen receptor (AR) signaling activates topoisomerase 2A (TOP2A) during DNA replication in prostate cancer cells, and Speckle-type brac/Tramtrack/Broad complex (BTB)/POZ protein (SPOP)-dependent removal of TOP2A from the TOP2A-DNA cleavage complex is necessary for the completion of DNA replication
Expression of prostate cancer-associated SPOP mutants caused the accumulation of double-strand breaks (DSBs) in prostate cancer cells in the absence of exogenous DNA damage stresses [38]
Summary
Ubiquitination is a post-translational modification that results in the addition of ubiquitin molecules to a protein in eukaryotes. When ubiquitin attaches to the N-terminus methionine of another ubiquitin, a linear ubiquitin chain forms [3] These ubiquitin codes determine the physiological functions of each polyubiquitin chain (e.g., K48-polyubiquitination in proteasomal degradation, M1-polyubiquitination in NF-κB signaling, K11-polyubiquitination in signal transduction, K63-polyubiquitination in the DNA damage response, K33-polyubiquitination in membrane trafficking) [4,5,6,7,8]. BTBPs recognize their substrate proteins and interact with the N-terminus of CUL3, leading to their ubiquitination [14]. SPOP mutants associated with prostate cancer fail to interact with and ubiquitinate their substrates, leading to the accumulation of oncogenic substrate proteins such as androgen receptor (AR), BRD2, and BRD4 [22,23,24,25]. Dysregulation of DNA damage response and DNA replication often generates genome instability, we suggest that SPOP prevents the generation of genome instability
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