title: Replication stress links structural and numerical cancer chromosomal instability.
abstract: Cancer chromosomal instability (CIN) results in an increased rate of change of chromosome number and structure and generates intratumour heterogeneity. CIN is observed in most solid tumours and is associated with both poor prognosis and drug resistance. Understanding a mechanistic basis for CIN is therefore paramount. Here we find evidence for impaired replication fork progression and increased DNA replication stress in CIN(+) colorectal cancer (CRC) cells relative to CIN(-) CRC cells, with structural chromosome abnormalities precipitating chromosome missegregation in mitosis. We identify three new CIN-suppressor genes (PIGN (also known as MCD4), MEX3C (RKHD2) and ZNF516 (KIAA0222)) encoded on chromosome 18q that are subject to frequent copy number loss in CIN(+) CRC. Chromosome 18q loss was temporally associated with aneuploidy onset at the adenoma-carcinoma transition. CIN-suppressor gene silencing leads to DNA replication stress, structural chromosome abnormalities and chromosome missegregation. Supplementing cells with nucleosides, to alleviate replication-associated damage, reduces the frequency of chromosome segregation errors after CIN-suppressor gene silencing, and attenuates segregation errors and DNA damage in CIN(+) cells. These data implicate a central role for replication stress in the generation of structural and numerical CIN, which may inform new therapeutic approaches to limit intratumour heterogeneity.
authors: Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, UK.
authors: Rebecca A
authors: RA
authors: Burrell
authors: Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, UK.
authors: Sarah E
authors: SE
authors: McClelland
authors: Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, UK.|University of Applied Sciences, Mathematics and Techniques, Remagen, Germany.
authors: David
authors: D
authors: Endesfelder
authors: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors: Petra
authors: P
authors: Groth
authors: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors: Marie-Christine
authors: MC
authors: Weller
authors: Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, UK.
authors: Nadeem
authors: N
authors: Shaikh
authors: Molecular and Population Genetics and NIHR Biomedical Research Centre, The Wellcome Trust Centre for Human Genetics, Oxford, UK.
authors: Enric
authors: E
authors: Domingo
authors: Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, UK.
authors: Nnennaya
authors: N
authors: Kanu
authors: Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, UK.
authors: Sally M
authors: SM
authors: Dewhurst
authors: Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, UK.
authors: Eva
authors: E
authors: Gronroos
authors: Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, UK.|UCL Cancer Institute, Paul O'Gorman Building, Huntley St., London, UK.
authors: Su Kit
authors: SK
authors: Chew
authors: Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, UK.
authors: Andrew J
authors: AJ
authors: Rowan
authors: University of Applied Sciences, Mathematics and Techniques, Remagen, Germany.
authors: Arne
authors: A
authors: Schenk
authors: Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel.
authors: Michal
authors: M
authors: Sheffer
authors: Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, UK.
authors: Michael
authors: M
authors: Howell
authors: University of Applied Sciences, Mathematics and Techniques, Remagen, Germany.
authors: Maik
authors: M
authors: Kschischo
authors: Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, UK.
authors: Axel
authors: A
authors: Behrens
authors: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors: Thomas
authors: T
authors: Helleday
authors: Danish Cancer Society Research Center, Strandboulevarden 49, Copenhagen, Denmark.|Institute of Molecular and Translational Medicine, Palacky University Olomouc, Czech republic.
authors: Jiri
authors: J
authors: Bartek
authors: Molecular and Population Genetics and NIHR Biomedical Research Centre, The Wellcome Trust Centre for Human Genetics, Oxford, UK.
authors: Ian P
authors: IP
authors: Tomlinson
authors: Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, UK.|UCL Cancer Institute, Paul O'Gorman Building, Huntley St., London, UK.
authors: Charles
authors: C
authors: Swanton
mesh_terms: D000782:Aneuploidy; D045744:Cell Line, Tumor; D043171:Chromosomal Instability / Q000187:drug effects / Q000235:genetics*; D020090:Chromosome Segregation / Q000187:drug effects / Q000235:genetics; D002887:Chromosomes, Human, Pair 18 / Q000187:drug effects / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D056915:DNA Copy Number Variations / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D004261:DNA Replication / Q000187:drug effects / Q000235:genetics*; D017353:Gene Deletion; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D009705:Nucleosides / Q000494:pharmacology; D010770:Phosphotransferases / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics
chemical_list: C515359:MEX3C protein, human; D009705:Nucleosides; D016601:RNA-Binding Proteins; C561296:PIGN protein, human; D010770:Phosphotransferases