RECQ5 Helicase Cooperates with MUS81 Endonuclease in Processing Stalled Replication Forks at Common Fragile Sites during Mitosis

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. 2017. RECQ5 Helicase Cooperates with MUS81 Endonuclease in Processing Stalled Replication Forks at Common Fragile Sites during Mitosis. Molecular Cell. 66 (5), pp. 658-671. doi:10.1016/j.molcel.2017.05.006

TitleRECQ5 Helicase Cooperates with MUS81 Endonuclease in Processing Stalled Replication Forks at Common Fragile Sites during Mitosis
AuthorsDi 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.
Abstract

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.

KeywordsMUS81; RAD51 filament; RECQ5; common fragile sites; genomic instability; mitotic DNA synthesis; replication stress
JournalMolecular Cell
Journal citation66 (5), pp. 658-671
ISSN1097-2765
Year2017
PublisherCell Press
Digital Object Identifier (DOI)doi:10.1016/j.molcel.2017.05.006
Publication dates
Published01 Jun 2017

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