Role of Nudix-Hydrolase ASMTL in Modulating Mitochondrial Biogenesis of Cancer Cells

Abstract

Cancer cells have enhanced DNA biosynthesis, rendering them susceptible to nucleotide modifications that enter the cellular nucleotide pool during repair or DNA degradation. These modified nucleotides can then be incorporated into newly synthesized DNA, resulting in random mutations or, when overwhelming into DNA damage, culminating into apoptosis, which is the desired effect of anti-cancer chemotherapy. Human cells contain nucleotide sanitation enzymes like ASMTL, which prevent incorporating the non-canonical nucleotides into newly synthesized DNA by removing them from the nucleotide pool, thereby relieving cancer cells from proliferative stress-induced mutations and apoptosis, representing an attractive target for anti-cancer chemotherapy. To identify ASMTL as a target for anti-cancer treatment, we investigated the ASMTL requirement for cancer survival in human cancer cell lines and patients, where ASMTL depletion decreased survival. This decrease in cell survival correlated with 14-3-3 interaction-dependent mitochondrial localization of ASMTL. Analyzing mitochondrial function suggests that ASMTL is imperative in the TP53 dependent BAX-BCL2 pathway, which is turned on by inefficient repair of mtDNA damage. Furthermore, after screening 2040 compounds, we identify small molecules TFBQ and TFHQ as ASMTL inhibitors that potently and selectively engage the ASMTL protein after occupying putative ASMTL MAF active site and impeding ASMTL-14-3-3 interaction. Finally, ASMTL is validated as an anti-cancer target in vivo where ASMTL knockout or inhibition triggers apoptosis and decreased metastasis in xenografts. This study collectively exemplifies the non-oncogene addiction concept for cancer treatment and validates ASMTL as phenotypically lethal to carcinomas.