DNA Replication Stress Drives Chromosomal Instability

Chromosomal instability (CIN) in cancer cells is associated with changes in chromosome structure and number that result in increased segregation errors during cell division and promote intratumoral heterogeneity in solid tumors such as colorectal cancer. Both mitotic and premitotic defects have been proposed to contribute to CIN, but the underlying mechanisms and genetic basis of this instability remain unclear. Burrell and colleagues found that structural chromosome abnormalities predominated in CIN-positive colorectal cancer cells in the absence of mitotic dysfunction, suggesting that premitotic defects may lead to segregation errors in these cells. Indeed, DNA replication fork progression was impaired in CIN-positive cells and accompanied by increased activation of the DNA damage response, indicative of replication stress. Consistent with these observations, activation of replication stress in CIN-negative cells stimulated structural and numerical chromosomal changes. The increase in replication stress in CIN-positive colorectal cancer cell lines and aneuploid tumors was correlated with recurrent somatic copy-number loss of a region of chromosome 18q, which contained 3 putative CIN-suppressor genes, phosphatidylinositol glycan anchor biosynthesis, class N (PIGN), MEX3C, and zinc finger protein 516 (ZNF516). Silencing of each gene in CIN-negative cells triggered segregation errors, including both structural and numerical chromosomal aberrations. Furthermore, CIN-suppressor gene downregulation impaired DNA replication fork progression and increased prometaphase DNA damage and other cellular hallmarks of replication stress prior to chromosome missegregation. Reduction of replication stress–associated DNA damage via supplementation with nucleosides reversed the increased segregation error frequency induced by silencing of these suppressor genes in CIN-negative cells or by loss of chromosome 18q in CIN-positive cells. These findings identify 18q loss and replication stress as drivers of CIN in colorectal cancer, and potentially in other solid tumors, and suggest that inhibition of replication stress may limit tumor heterogeneity and prevent drug resistance.

Burrell RA, McClelland SE, Endesfelder D, Groth P, Weller MC, Shaikh N, et al. Replication stress links structural and numerical cancer chromosomal instability. Nature 2013;494:492–6.

Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.