The poly(ADP-ribose) polymerase 1 (PARP-1) enzyme has received much attention in the last decade due to its promising role in cancer therapeutics. Despite the expanding use of PARP inhibitors in cancer therapy, little is known about PARP-1 tissue distribution. Our study provides a detailed survey of PARP-1 tissue and cellular distribution using well-preserved cynomolgus monkey organs and a well-characterized, highly specific monoclonal PARP-1 antibody. Overall, PARP-1 was detected in most organs, but its distribution was restricted to specific cells within each tissue, suggesting that PARP-1 expression is tightly regulated. The strongest expression was in the pituitary, the ovary, the male adrenal gland, and the thymus. One of the key findings of this study was the stronger expression of PARP-1 in proliferating cells rather than mature cells. This observation not only provides clues to the importance of PARP-1 in processes such as DNA replication and transcription in these cell types, but it also provides the basis for further investigation into the effects of its inhibition in the context of malignancy. Overall, this study greatly expands the current knowledge of PARP-1 tissue expression, enabling the identification of tissues where PARP inhibition may be most efficacious.

Nucleotide sugar-dependent glycosyltransferases (UGTs) are critical to the homeostasis of endogenous metabolites and the detoxification of xenobiotics. Their impact on the cell metabolome remains unknown. Cellular metabolic changes resulting from human UGT expression were profiled by untargeted metabolomics. The abundant UGT1A1 and UGT2B7 were studied as UGT prototypes along with their alternative (alt.) splicing-derived isoforms displaying structural differences. Nineteen biochemical routes were modified, beyond known UGT substrates. Significant variations in glycolysis and pyrimidine pathways, and precursors of the co-substrate UDP-glucuronic acid were observed. Bioactive lipids such as arachidonic acid and endocannabinoids were highly enriched by up to 13.3-fold (p < 0.01) in cells expressing the canonical enzymes. Alt. UGT2B7 induced drastic and unique metabolic perturbations, including higher glucose (18-fold) levels and tricarboxylic acid cycle (TCA) cycle metabolites and abrogated the effects of the UGT2B7 canonical enzyme when co-expressed. UGT1A1 proteins promoted the accumulation of branched-chain amino acids (BCAA) and TCA metabolites upstream of the mitochondrial oxoglutarate dehydrogenase complex (OGDC). Alt. UGT1A1 exacerbated these changes, likely through its interaction with the OGDC component oxoglutarate dehydrogenase-like (OGDHL). This study expands the breadth of biochemical pathways associated with UGT expression and establishes extensive connectivity between UGT enzymes, alt. proteins and other metabolic processes.

In chronic lymphocytic leukemia (CLL), an elevated glycosyltransferase UGT2B17 expression (UGT2B17^HI) identifies a subgroup of patients with shorter survival and poor drug response. We uncovered a mechanism, possibly independent of its enzymatic function, characterized by an enhanced expression and signaling of the proximal effectors of the pro-survival B cell receptor (BCR) pathway and elevated Bruton tyrosine kinase (BTK) phosphorylation in B-CLL cells from UGT2B17^HI patients. A prominent feature of B-CLL cells is the strong correlation of UGT2B17 expression with the adverse marker ZAP70 encoding a tyrosine kinase that promotes B-CLL cell survival. Their combined high expression levels in the treatment of naïve patients further defined a prognostic group with the highest risk of poor survival. In leukemic cells, UGT2B17 knockout and repression of ZAP70 reduced proliferation, suggesting that the function of UGT2B17 might involve ZAP70. Mechanistically, UGT2B17 interacted with several kinases of the BCR pathway, including ZAP70, SYK, and BTK, revealing a potential therapeutic vulnerability. The dual SYK and JAK/STAT6 inhibitor cerdulatinib most effectively compromised the proliferative advantage conferred by UGT2B17 compared to the selective BTK inhibitor ibrutinib. Findings point to an oncogenic role for UGT2B17 as a novel constituent of BCR signalosome also connected with microenvironmental signaling.

Germline deletions of UDP-glycosyltransferase (UGT) UGT2B17 and UGT2B28 genes are common in human populations, yet their association with aging remains unclear. In this exploratory study, we analyzed data from 12,934 participants, mostly Caucasian, in the Canadian Longitudinal Study on Aging (CLSA) to assess cross-sectional and prospective associations between UGT deficiencies and aging-related health outcomes, including mortality, multimorbidity, allostatic load, disease burden and polypharmacy. Sex-specific associations emerged from cross-sectional analyses: UGT2B17-deficient males were less likely to report arthritis (adjusted odds ratio (OR_adj) = 0.73, 95% confidence interval (0.58-0.92), P = 0.008), UGT2B17-deficient females were less likely to report neurological problems (OR_adj = 0.69 (0.51-0.91), P = 0.01), and UGT2B28-deficient females were less likely to report thyroid disorders (OR_adj = 0.50 (0.29-0.82), P = 0.009). Despite these associations, multimorbidity remained prevalent across all groups and no significant associations were observed with all-cause mortality or longevity. Physiological dysregulation, assessed by the allostatic load index, was more prevalent in males. Among males aged ≥ 65, UGT2B28-deficiency was associated with reduced high dysregulation compared to UGT-proficient males (40.0% vs. 53.0%, P = 0.05), whereas UGT2B17 deficiency was associated with a higher prevalence in males (60.4% vs. 53.0%, P = 0.03). In addition, UGT2B17-deficient males had a lower prevalence of polypharmacy than UGT-proficient males (9.3% vs. 13.9%; P = 0.02). Overall, these findings indicate sex-specific associations between UGT2B17 and UGT2B28 deletions and selected healthspan-related phenotypes, suggesting that UGT-related genetic variation may modulate physiological pathways relevant to aging. Given the exploratory nature of this study and its reliance on prevalence data, the results are intended to be hypothesis-generating and will require confirmation in longer-term longitudinal studies.