Transfer RNA (tRNA) is best known to function in ribosome-mediated protein synthesis. However, in a less known role, arginyl-tRNA is essential for catalyzing a unique and poorly understood protein post-translational modification, namely arginylation, that regulates protein turnover. In this arginylation reaction, ATE1 (Arginyltransferase 1) facilitates arginine transfer to protein targets using a mechanism that depends on, and is selective for, arginyl-tRNA(Arg) as the donor cofactor. ATE1-mediated protein arginylation was identified on hundreds of proteins and is recognized as a global regulator of eukaryotic cellular processes, including embryogenesis, stress responses, and aging. Deregulation of ATE1 is found in patients with Parkinson’s disease and metastatic prostate, liver, and skin cancers. Nonetheless, how ATE1 (and other aminoacyl-tRNA transferases) hijacks tRNA from the highly efficient ribosomal protein synthesis pathways and catalyzes the arginylation reaction remains a mystery. Ongoing research in the lab aims at understanding the structural mechanisms of protein arginylation (Nat Commun 2023), its crosstalk with canonical translation, and its regulation and cellular functions.

Certain components in human cells, such as protein aggregates and damaged organelles, can be specifically removed through receptor-mediated autophagy. We currently focus on one such receptor, SQSTM1/p62, which mediates cell proliferation, survival, and death through multiple signaling pathways, including mTORC1 activation and autophagy. Accumulation and misregulation of p62 have been linked to tumor formation, progression, and resistance to therapy, thus p62 is emerging as a new therapeutic target in cancer treatment. Our past research uncovered the mechanism by which p62 selectively senses arginylated proteins that are generated in response to ER-stress (Nat Commun 2019; Autophagy 2020). Ongoing research in the lab aims at understanding the basic biology of p62, including how p62 senses/integrates various stress signals and makes certain cellular decisions, such as cell survival and death. This knowledge could lead to new approaches in combination cancer therapy for treating multiple myeloma and other tumor types.

In human cells, histone proteins, which compact genomic DNA, can be heavily decorated with post-translational modifications (PTMs) which are also referred to as epigenetic marks. The chemical nature and location of these marks correlate with every aspect of DNA-templated processes, ranging from DNA replication required for cell proliferation to gene transcription and DNA damage repair required for cell survival. Deregulation of epigenetic mechanisms is closely linked to cancer, metabolic disorders, and aging. Our past research reinforced the idea that epigenetic marks are specifically recognized, and deposition of PTMs is likely an ordered process, suggesting crosstalk among histone PTMs and epigenetic regulators (NSMB 2018; Nat Commun 2018; PNAS 2019; Nat Commun 2019). This interplay is fundamental for proper chromatin structure, gene expression, and DNA damage response, therefore vitally important during normal development and in disease. Our knowledge in this field has grown rapidly in the past few years, however, compared to dozens of PTMs on histones and hundreds of proteins interacting with them, it is still a long way ahead to decipher the epigenetic language accurately. Our ultimate goal is to have a chemical comprehension of how epigenetic marks regulate nuclear processes and apply this knowledge in drug development for personalized medicine.

We made interesting observations while examining the functions of chromatin remodelers/modifiers and found many of them form nuclear condensates with liquid/gel-like properties. The number and size of some condensates are regulated through the cell cycle; whereas for others, condensates formation attenuates their catalytic activity (iSicence 2019; JMB 2020; Nat Commun 2021). This body of work shows an exciting new layer of chromatin regulation through forming local compartments by phase transition. We investigate the content, regulation, and functional significance of these membrane-less organelles in vitro and in cells. Our ultimate goal is to develop a comprehensive view of how cells control condensates formation/disassembly as well as how condensates regulate biological reactions.