RECQ5 Helicase Cooperates with MUS81 Endonuclease in Processing Stalled Replication Forks at Common Fragile Sites during Mitosis
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RECQ5 Helicase Cooperates with MUS81 Endonuclease in Processing Stalled Replication Forks at Common Fragile Sites during Mitosis. / Di Marco, Stefano; Hasanova, Zdenka; Kanagaraj, Radhakrishnan; Chappidi, Nagaraja; Altmannova, Veronika; Menon, Shruti; Sedlackova, Hana; Langhoff, Jana; Surendranath, Kalpana; Hühn, Daniela; Bhowmick, Rahul; Marini, Victoria; Ferrari, Stefano; Hickson, Ian D; Krejci, Lumir; Janscak, Pavel.
In: Molecular Cell, Vol. 66, No. 5, 01.06.2017, p. 658-671.e8.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - RECQ5 Helicase Cooperates with MUS81 Endonuclease in Processing Stalled Replication Forks at Common Fragile Sites during Mitosis
AU - Di Marco, Stefano
AU - Hasanova, Zdenka
AU - Kanagaraj, Radhakrishnan
AU - Chappidi, Nagaraja
AU - Altmannova, Veronika
AU - Menon, Shruti
AU - Sedlackova, Hana
AU - Langhoff, Jana
AU - Surendranath, Kalpana
AU - Hühn, Daniela
AU - Bhowmick, Rahul
AU - Marini, Victoria
AU - Ferrari, Stefano
AU - Hickson, Ian D
AU - Krejci, Lumir
AU - Janscak, Pavel
N1 - Copyright © 2017 Elsevier Inc. All rights reserved.
PY - 2017/6/1
Y1 - 2017/6/1
N2 - 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.
AB - 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.
KW - Binding Sites
KW - Chromosomal Instability
KW - Chromosome Fragile Sites
KW - Chromosome Segregation
KW - Cyclin-Dependent Kinases
KW - DNA
KW - DNA Damage
KW - DNA Repair
KW - DNA-Binding Proteins
KW - Endodeoxyribonucleases
KW - Endonucleases
KW - HEK293 Cells
KW - HeLa Cells
KW - Humans
KW - Mitosis
KW - Phosphorylation
KW - Protein Binding
KW - RNA Interference
KW - Rad51 Recombinase
KW - RecQ Helicases
KW - Replication Origin
KW - Time Factors
KW - Transfection
KW - Journal Article
U2 - 10.1016/j.molcel.2017.05.006
DO - 10.1016/j.molcel.2017.05.006
M3 - Journal article
C2 - 28575661
VL - 66
SP - 658-671.e8
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 5
ER -
ID: 185901602