Target Proteins
POP1
POP1 (Processing of Precursors-1) is a ribonuclease that is most well-known for its vital role in the RNase P and MRP complexes. These highly conserved complexes have vital roles in the cell, as RNase P matures the 5’ ends of tRNA and RNase MRP cleaves pre-rRNA (1,2). In both of these, POP1 binds simultaneously with POP6/7 to the RNA components of the complex. This provides protection to specific parts of the RNA, encouraging proteins like RNase A and RNase VI to cleave the unprotected regions (3).
Recently, POP1 has been implicated in the formation of the telomerase complex. It is suggested to use its RNA binding ability to stabilise TERC (Telomerase RNA Component), in order for the telomerase complex to be recruited to the RNA (4). This has been proposed via the P3 domain of the RNA, which is significantly homologous between TLC1, the specific RNA strand of TERC that POP1 would bind to, NME1, the RNA portion of RNase MRP, and RPR1, the RNA component of RNase P. In fact, these P3 regions have been said to be functionally interchangeable in yeast (5). These regions are highly conserved throughout eukaryotes, so it is thought that this discovery reflects the human structures of these proteins. In fact, POP1 upregulation has been found as a factor in breast cancer development, theoretically because of the upregulation of telomerase and extension of the telomeres of the cancer cell (4). This makes it a great target for our PROTAC design.
POP1’s Saccharomyces cerevisiae homolog of the same name shows very close structural and functional homology as the human protein. The two homologs have also been shown to be evolutionarily related (6).
ATM
Ataxia-Talengiectasia Mutated (ATM) is a serine/thronine pleiotropic protein kinase that plays a key role in survival (7). Activation of this protein is involved in cell cycle checkpoint signalling, double strand break (DSB) repair, apoptosis initiation, and genome surveillance (8,9). Most importantly, ATM mediates the preferential recruitment of the telomerase complex to shorter telomeres (8–12).
ATM is part of the phosphatidylinositol 3-kinase-related kinase (PIKK) family of serine/threonine protein kinases (13). Members of this family share similar structural and functional properties, and each have conserved sequence homology in their C-terminal kinase domain, FAT domain, and and FATC domain (7,14).
ATM’s close yeast homolog, Tel1, has been shown to be responsible for the preferential recuruitment of the telomerase complex to shorter telomeres in Saccharomyces cerevisiae (7,15–17). Fritz and colleagues (2000) showed that human cells derived from ataxia-talengiectasia patients showed relieved symptoms in response to overexpression of Tel1, the yeast homologue (18). This demonstrates their structural and functional homology.