Journal Article

Replication stress activates DNA repair synthesis in mitosis

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

2015

Overview

Common fragile sites (CFSs) are difficult-to-replicate regions of eukaryotic genomes that are sensitive to replication stress and that require resolution by the MUS81–EME1 endonuclease to re-initiate POLD3-dependent DNA synthesis in early mitosis; this study defines the specific pathway of events causing the CFS fragility phenotype. Inbuilt chromosome fragility Common fragile sites (CFSs) are regions of eukaryotic genomes that are sensitive to DNA replication stressors. They are stably maintained and replicated in the human genome most of the time, but have been associated with some cancers and genetic disease. CFS 'expression' was shown recently to be a programmed event promoted by the MUS81 endonuclease, rather than disruption of the chromosome structure caused by mechanical forces in mitosis. Ian Hickson and colleagues have now defined the specific chain of events causing CFSs. They describe a pathway of unscheduled DNA synthesis regulated by the MUS81 endonuclease, the POLD3 subunit of DNA polymerase delta and the prophase pathway in early mitosis. Oncogene-induced DNA replication stress has been implicated as a driver of tumorigenesis 1 . Many chromosomal rearrangements characteristic of human cancers originate from specific regions of the genome called common fragile sites (CFSs) 2 , 3 , 4 , 5 . 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 6 . The MUS81–EME1 structure-specific endonuclease promotes the appearance of chromosome gaps or breaks at CFSs following replicative stress 7 , 8 , 9 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/337/151/2357 / 631/67/68 / 631/80/641/151/2357 / 631/80/641/2002 / Carcinogenesis - genetics / Cell division / Cell Line, Tumor / Cells / Chromosomal Instability / Chromosome Fragile Sites / Chromosome Segregation / Chromosomes / Deoxyribonucleic acid / DNA / DNA Polymerase III - metabolism / DNA repair / DNA Repair - physiology / DNA replication / DNA Replication - genetics / DNA synthesis / DNA-Binding Proteins - metabolism / Endodeoxyribonucleases - genetics / Endodeoxyribonucleases - metabolism / Endonucleases - metabolism / Gene Expression Regulation, Neoplastic / HCT116 Cells / HeLa Cells / HT29 Cells / Humanities and Social Sciences / Humans / letter / Mitosis / Mitosis - genetics / Models, Biological / multidisciplinary / Nondisjunction, Genetic - genetics / Physiological aspects / Science / Stress, Physiological - genetics / Tumorigenesis