Replication stress activates DNA repair synthesis in mitosis
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Replication stress activates DNA repair synthesis in mitosis. / Minocherhomji, Sheroy; Ying, Songmin; Bjerregaard, Victoria A; Bursomanno, Sara; Aleliunaite, Aiste; Wu, Wei; Mankouri, Hocine W; Shen, Huahao; Liu, Ying; Hickson, Ian D.
In: Nature, Vol. 528, No. 7581, 10.12.2015, p. 286-90.Research output: Contribution to journal › Letter › Research › peer-review
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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
VL - 528
SP - 286
EP - 290
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7581
ER -
ID: 155604887