RECQ4-MUS81 interaction safeguards hard-to-replicate regions to prevent genome instability and Rothmund-Thomson syndrome

Abstract Replication stress, resulting from hard-to-replicate regions, leads to the accumulation of replication intermediates that need to be processed to ensure successful chromosome segregation. Here we show that RECQ4 physically interacts with MUS81 to target it to DNA substrates and enhance its endonuclease activity. Loss of RECQ4 or its interaction with MUS81 results in chromosomal segregation defects, including the accumulation of micronuclei and anaphase bridges along with ultrafine bridges (UFBs). Our data further demonstrate that the RECQ4/MUS81 interaction plays a critical role in processing replication/recombination intermediates at telomeres, especially in ALT-positive cells where MUS81 foci primarily colocalise with telomeres. We also observed reminiscent phenotypes for Rothmund-Thomson syndrome-associated mutation producing a truncated version of RECQ4 that disrupts interaction with MUS81, suggesting the importance of this interaction and its function in the development of RTS. Our findings demonstrate the essential role of RECQ4/MUS81 interaction in alleviating replication stress build-up at hard-to-replicate regions and highlight the potential implications of this interaction in human disease.