The POLD1^R689W variant increases the sensitivity of colorectal cancer cells to ATR and CHK1 inhibitors.

ABSTRACT: Inhibition of the kinase ATR, a central regulator of the DNA damage response, eliminates subsets of cancer cells in certain tumors. As previously shown, this is at least partly attributable to synthetic lethal interactions between ATR and POLD1, the catalytic subunit of the polymerase δ. Various POLD1 variants have been found in colorectal cancer, but their significance as therapeutic targets for ATR pathway inhibition remains unknown. Using CRISPR/Cas9 in the colorectal cancer cell line DLD-1, which harbors four POLD1 variants, we established heterozygous POLD1-knockout clones with exclusive expression of distinct variants to determine the functional relevance of these variants individually by assessing their impact on ATR pathway activation, DNA replication, and cellular sensitivity to i

SUBMITTER: Job A 

PROVIDER: S-EPMC7641191 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature