Research Highlights
Deciphering purinosome assembly mechanism to open a new direction for cancer metabolism research

Metabolic reprogramming is a hallmark of cancer. Cancer cells alter various cellular metabolism pathways to meet the high demand on bioenergetics and biosynthesis and to adapt the harsh tumor microenvironment. However, it remains unclear whether other strategies of metabolic alterations can be exploited by cancer cells for maintaining their proliferation and survival.

Purinosome represents a type of biomolecular condensates and its formation enhances DNPS pathway flux. However, the assembly mechanism and pathophysiological functions of purinosome are completely unexplored. Dr. Ruey-Hwa Chen’s group has identified the first purinosome assembly mechanism. Under several purinosome-inducing cues, ASB11-based ubiquitin E3 ligase is upregulated to trigger a k6-linked polyubiquitination of PAICS, an octameric enzyme in the DNPS pathway. The ubiquitinated PAICS recruits a ubiquitin-binding and disordered protein UBAP2 to confer multivalent binding, thereby inducing liquid-liquid phase separation and purinosome assembly. By expressing a high level of ASB11, melanoma cells form purinosome constitutively, to which they are addicted for supporting their proliferation and viability. This study uncovers the impacts of metabolic enzyme compartmentalization on human malignancies and highlights a potential of purinosome targeting as an anti-cancer strategy.

The co-first authors of this study are Ph.D. student Ming-Chieh Chou and Research Assistant Yi-Husan Wang. This study has been published in Molecular Cell.

Article: PAICS ubiquitination recruits UBAP2 to trigger phase separation for purinosome assembly

Article link: https://doi.org/10.1016/j.molcel.2023.09.028

Authors: Chou MC, Wang YH, Chen FY, Kung CY, Wu KP, Kuo JC, Chan SJ, Cheng ML, Lin CY, Chou YC, Ho MC, Firestine S, Huang JR, Chen RH*