Replication stress activates DNA repair synthesis in mitosis

TY - JOUR

T1 - Replication stress activates DNA repair synthesis in mitosis

AU - Minocherhomji, Sheroy

AU - Ying, Songmin

AU - Bjerregaard, Victoria A

AU - Bursomanno, Sara

AU - Aleliunaite, Aiste

AU - Wu, Wei

AU - Mankouri, Hocine W

AU - Shen, Huahao

AU - Liu, Ying

AU - Hickson, Ian D

PY - 2015/12/10

Y1 - 2015/12/10

N2 - 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.

AB - 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.

KW - Carcinogenesis

KW - Cell Line, Tumor

KW - Chromosomal Instability

KW - Chromosome Fragile Sites

KW - Chromosome Segregation

KW - DNA Polymerase III

KW - DNA Repair

KW - DNA Replication

KW - DNA-Binding Proteins

KW - Endodeoxyribonucleases

KW - Endonucleases

KW - Gene Expression Regulation, Neoplastic

KW - HCT116 Cells

KW - HT29 Cells

KW - HeLa Cells

KW - Humans

KW - Mitosis

KW - Models, Biological

KW - Nondisjunction, Genetic

KW - Stress, Physiological

U2 - 10.1038/nature16139

DO - 10.1038/nature16139

M3 - Letter

C2 - 26633632

SN - 0028-0836

VL - 528

SP - 286

EP - 290

JO - Nature

JF - Nature

IS - 7581

ER -