Abstract of the talk// Cells are the fundamental units of life, yet how they organize their internal components into dynamic, functional architectures remains one of biology’s most profound open questions. Hari’s research seeks to uncover and predict how such organization emerges at the mesoscale, the level between molecules and whole cells where biological decision-making arises.

During his PhD at LMU, Munich, he investigated how chromatin remodellers integrate molecular signals with mesoscale organization. He discovered that the oncogene ALC1 (Amplified in Liver Cancer 1) is an auto-inhibited enzyme activated by DNA damage-induced poly-ADP-ribose (PAR) signalling, revealing how modular allostery enables robust DNA damage responses and offers druggable opportunities.

Building on this foundation, his postdoctoral research at the MPI-CBG in Dresden explores how biomolecular condensates govern protein function through mesoscale organization, and how their disruption leads to human disease. Using a systematic screen of the TRIM ubiquitin ligase family, the team finds that many TRIM proteins exhibit global mesoscale organization through dynamic condensates. Through in cellulo condensatography, it charts nuclear TRIM condensation and characterizes TRIM8 syndrome, a neuro-renal disorder caused by C-terminal intrinsically disordered region (IDR) truncations. These mutations disrupt condensate formation, proteasomal regulation, and NFκB signalling, leading to podocyte dysfunction. Remarkably, IDR complementation restores condensate formation and rescues cellular signalling. Additionally, Hari and colleagues developed PICNIC, a machine learning classifier that predicts condensate-forming proteins independent of structural disorder, providing a powerful tool for the broader scientific community. These findings establish a multi-scale framework for understanding human condensatopathies, linking molecular sequence, cellular organization, and physiological function.