|Title||RECQ5 Helicase Cooperates with MUS81 Endonuclease in Processing Stalled Replication Forks at Common Fragile Sites during Mitosis|
|Authors||Di Marco, S., Hasanova, Z., Kanagaraj, R., Chappidi, N., Altmannova, V., Menon, S., Sedlackova, H., Langhoff, J., Surendranath, K., Hühn, D., Bhowmick, R., Marini, V., Ferrari, S., Hickson, I.D., Krejci, L. and Janscak, P.|
The MUS81-EME1 endonuclease cleaves late replication intermediates at common fragile sites (CFSs) during early mitosis to trigger DNA-repair synthesis that ensures faithful chromosome segregation. Here, we show that these DNA transactions are promoted by RECQ5 DNA helicase in a manner dependent on its Ser727 phosphorylation by CDK1. Upon replication stress, RECQ5 associates with CFSs in early mitosis through its physical interaction with MUS81 and promotes MUS81-dependent mitotic DNA synthesis. RECQ5 depletion or mutational inactivation of its ATP-binding site, RAD51-interacting domain, or phosphorylation site causes excessive binding of RAD51 to CFS loci and impairs CFS expression. This leads to defective chromosome segregation and accumulation of CFS-associated DNA damage in G1 cells. Biochemically, RECQ5 alleviates the inhibitory effect of RAD51 on 3'-flap DNA cleavage by MUS81-EME1 through its RAD51 filament disruption activity. These data suggest that RECQ5 removes RAD51 filaments stabilizing stalled replication forks at CFSs and hence facilitates CFS cleavage by MUS81-EME1.
|Keywords||MUS81; RAD51 filament; RECQ5; common fragile sites; genomic instability; mitotic DNA synthesis; replication stress|
|Journal citation||66 (5), pp. 658-671|
|Digital Object Identifier (DOI)||doi:10.1016/j.molcel.2017.05.006|
|Published||01 Jun 2017|