Replication stress activates DNA repair synthesis in mitosis

Research output: Contribution to journalLetterResearchpeer-review

Sheroy Minocherhomji, Songmin Ying, Victoria A Bjerregaard, Sara Bursomanno, Aiste Aleliunaite, Wei Wu, Hocine W Mankouri, Huahao Shen, Ying Liu, Ian D Hickson

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.

Original languageEnglish
JournalNature
Volume528
Issue number7581
Pages (from-to)286-90
Number of pages5
ISSN0028-0836
DOIs
Publication statusPublished - 10 Dec 2015

    Research areas

  • Carcinogenesis, Cell Line, Tumor, Chromosomal Instability, Chromosome Fragile Sites, Chromosome Segregation, DNA Polymerase III, DNA Repair, DNA Replication, DNA-Binding Proteins, Endodeoxyribonucleases, Endonucleases, Gene Expression Regulation, Neoplastic, HCT116 Cells, HT29 Cells, HeLa Cells, Humans, Mitosis, Models, Biological, Nondisjunction, Genetic, Stress, Physiological

ID: 155604887