Replication stress links structural and numerical cancer chromosomal instability


Session type:

Rebecca Burrell1, Sarah McClelland1,9, David Endesfelder1,2, Petra Groth3, Marie-Christine Weller3, Nadeem Shaikh1, Enric Domingo4, Nnennaya Kanu1,5, Sally Dewhurst1, Eva Groonroos1, Su Kit Chew1,5, Andrew Rowan1, Arne Schenk2, Michal Scheffer6, Michael Howell1, Maik Kschischo2, Axel Behrens1, Thomas Helleday3, Jiri Bartek7,8, Ian Tomlinson4
1CRUK, London, UK, 2University of Applied Sciences, Koblenz, Germany, 3Karolinska Insitutet, Stockholm, Sweden, 4The Wellcome trust Centre for Human Genetics, Oxford, UK, 5UCL Cancer Institute, London, UK, 6Weizmann Institute of Science, Rehovot, Israel, 7Danish Cancer Society Research Centre, Copenhagen, Denmark, 8Institute of Molecular and Translational Medicine, Olomouc, Czech Republic, 9Barts Cancer Institute, London, UK


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.


We combined genomics approaches with classical cell biology and high-resolution microscopy, in addition to DNA fibre assays in tissue culture cells.


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.