K63-linked ubiquitylation of RMI1 by RNF8 is essential to its recruitment to stalled forks. Arun R, Kumbhakar S, Kaur T, Kaur S, Sengupta S. Cell Mol Life Sci. 2026 Mar 5;83(1):153. doi: 10.1007/s00018-026-06156-7. PMID: 41784835.
Abstract
RMI1 forms an evolutionarily conserved complex known as the BTR complex along with BLM and TOP3A. This complex plays a crucial role in DNA repair, particularly in the resolution of Holiday Junction like intermediates which are formed during homologous recombination. Despite the crucial role of this complex, very little is known about the recruitment of RMI1 to the sites of DNA damage like stalled forks. Here we demonstrate that RMI1 is recruited to sites of replication stress in a ubiquitin-dependent manner. We identified an essential role of the RING-type E3 ubiquitin ligase, RNF8, in the recruitment of RMI1 to the sites of stalled replication through K63-linked polyubiquitylation at three lysine residues, Lys428, Lys453 and Lys566. This modification is crucial for the proper localization of RMI1 along with the entire BTR complex at these sites of DNA damage, thereby ensuring its downstream functions. Further, the ubiquitylation of RMI1 is essential for replication fork recovery. Taken together, this study deciphers how RNF8-dependent ubiquitylation cascade is recruited to the chromatin where it is involved in preserving genome stability.
