title: Replication stress activates DNA repair synthesis in mitosis.
abstract: Oncogene-induced DNA replication stress has been implicated as a driver of tumorigenesis. Many chromosomal rearrangements characteristic of human cancers originate from specific regions of the genome called common fragile sites (CFSs). CFSs are difficult-to-replicate loci that manifest as gaps or breaks on metaphase chromosomes (termed CFS 'expression'), particularly when cells have been exposed to replicative stress. The MUS81-EME1 structure-specific endonuclease promotes the appearance of chromosome gaps or breaks at CFSs following replicative stress. Here we show that entry of cells into mitotic prophase triggers the recruitment of MUS81 to CFSs. The nuclease activity of MUS81 then promotes POLD3-dependent DNA synthesis at CFSs, which serves to minimize chromosome mis-segregation and non-disjunction. We propose that the attempted condensation of incompletely duplicated loci in early mitosis serves as the trigger for completion of DNA replication at CFS loci in human cells. Given that this POLD3-dependent mitotic DNA synthesis is enhanced in aneuploid cancer cells that exhibit intrinsically high levels of chromosomal instability (CIN(+)) and replicative stress, we suggest that targeting this pathway could represent a new therapeutic approach.
authors.affiliation: Center for Chromosome Stability and Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Panum Institute, Blegdamsvej 3B, 2200 Copenhagen N, Denmark.
authors.forename: Sheroy
authors.initials: S
authors.lastname: Minocherhomji
authors.affiliation: Department of Respiratory and Critical Care Medicine of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.|Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou 310058, China.
authors.forename: Songmin
authors.initials: S
authors.lastname: Ying
authors.affiliation: Center for Chromosome Stability and Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Panum Institute, Blegdamsvej 3B, 2200 Copenhagen N, Denmark.
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Bjerregaard
authors.affiliation: Center for Chromosome Stability and Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Panum Institute, Blegdamsvej 3B, 2200 Copenhagen N, Denmark.
authors.forename: Sara
authors.initials: S
authors.lastname: Bursomanno
authors.affiliation: Center for Chromosome Stability and Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Panum Institute, Blegdamsvej 3B, 2200 Copenhagen N, Denmark.
authors.forename: Aiste
authors.initials: A
authors.lastname: Aleliunaite
authors.affiliation: Center for Chromosome Stability and Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Panum Institute, Blegdamsvej 3B, 2200 Copenhagen N, Denmark.
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.affiliation: Center for Chromosome Stability and Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Panum Institute, Blegdamsvej 3B, 2200 Copenhagen N, Denmark.
authors.forename: Hocine W
authors.initials: HW
authors.lastname: Mankouri
authors.affiliation: Department of Respiratory and Critical Care Medicine of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.|State Key Laboratory of Respiratory Disease (SKLRD), Guangzhou 510120, China.
authors.forename: Huahao
authors.initials: H
authors.lastname: Shen
authors.affiliation: Center for Chromosome Stability and Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Panum Institute, Blegdamsvej 3B, 2200 Copenhagen N, Denmark.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Center for Chromosome Stability and Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Panum Institute, Blegdamsvej 3B, 2200 Copenhagen N, Denmark.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Hickson
mesh_terms: D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D043171:Chromosomal Instability; D043283:Chromosome Fragile Sites; D020090:Chromosome Segregation; D004258:DNA Polymerase III / Q000378:metabolism; D004260:DNA Repair / Q000502:physiology*; D004261:DNA Replication / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D004706:Endodeoxyribonucleases / Q000235:genetics / Q000378:metabolism*; D004720:Endonucleases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis / Q000235:genetics*; D008954:Models, Biological; D009630:Nondisjunction, Genetic / Q000235:genetics; D013312:Stress, Physiological / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C435720:POLD3 protein, human; D004258:DNA Polymerase III; C507947:Eme1 protein, human; D004706:Endodeoxyribonucleases; D004720:Endonucleases; C498772:MUS81 protein, human