Research Field
Quality Control Mechanisms
Nucleic acid quality control safeguards genome integrity by detecting and resolving damage, errors, and stress.
Description
The integrity of DNA and RNA is continuously challenged by damage, errors, and environmental stress. This research area investigates the quality control mechanisms that preserve nucleic acid function, maintain genome stability, and support cellular viability. A central goal is to understand how cells recognize diverse forms of nucleic acid damage and coordinate robust responses despite the complexity and dynamic nature of these processes.
The research examines quality control pathways acting on both DNA and RNA, including mechanisms of lesion recognition, signal transduction, repair, surveillance, and stress responses. Particular emphasis is placed on understanding how different pathways cooperate to identify and resolve damaged or aberrant nucleic acids within complex cellular environments. The project also explores the organization of quality control machinery at the mesoscale and the role of nucleic acid–mediated assemblies in coordinating these responses. Together, these studies aim to establish fundamental principles of nucleic acid quality control and their implications for disease mechanisms and nucleic acid–based therapeutics.
Area B3
Publications
Recognition and remodelling of nucleosomes and hexasomes by the human INO80 complex.
Nucleic Acids Res. · 2026
Show abstract
The ATP-dependent INO80 chromatin remodeller slides and repositions nucleosomes to shape and maintain chromatin around gene regulatory elements and replication origins. Recent work uncovered capabilities of yeast and fungal INO80 to bind and slide hexasomes, but whether this is a universal feature is unknown. Here, we show that human INO80 also slides hexasomes as efficiently as H2A and H2A.Z nucleosomes. By determining a variety of structures of human INO80 bound to canonical and H2A.Z nucleosomes as well as hexasomes, we reveal a predominantly topological sensing of nucleosomal species with at least three positions depending on entry DNA unwrapping. INO80 spin-rotates around the nucleosomal core particle as a function of entry DNA unwrapping. Different degrees of unwrapped entry DNA lead to two different nucleosomal and one hexasomal locations of INO80, determined by binding of the Snf2 ATPase to entry point of extranucleosomal DNA at the nucleosome/hexasome core. Acidic patch binding by the INO80 subunit IES2 can differentiate between (sub)nucleosomal species, is important for nucleosome but not hexasome sliding, and may sense unwrapped exit DNA. These findings provide structural and mechanistic insights into how human INO80 remodels diverse chromatin substrates in a topology driven manner.
RNF25 confers mRNA damage tolerance by curbing activation of the integrated stress response.
Mol Cell. · 2026
Show abstract
Excessive RNA damage activates cellular stress responses, triggering cell death. However, pathways that negatively regulate RNA damage responses are largely uncharacterized. Using genetic screens, we find that the ubiquitin ligase RNF25 provides tolerance to RNA damage caused by the nucleoside analogue azacytidine, a chemotherapeutic agent used to treat acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Mechanistically, we show that azacytidine is incorporated into mRNA, where it causes lesions that stall elongating ribosomes, leading to cytotoxic activation of the GCN2-dependent integrated stress response (ISR). Furthermore, we establish that RNF25 prevents ISR hyperactivation by ubiquitylation of ribosomal protein eS31, thereby suppressing cell death upon azacytidine treatment. Our study reveals an mRNA damage tolerance mechanism that determines cellular survival in response to azacytidine, highlighting RNA damage-induced stress response as a potentially critical component of chemosensitivity in AML and MDS.