Reduced POLD3 Expression Induces DNA Damage and Telomere Shortening in Colorectal Cancer Cells: A Potential Mediator of Colorectal Cancer Risk Variants

Lower POLD3 expression in colorectal cancer cell line models is linked to increased DNA double-strand breaks and shortened telomeres, implicating impaired ALT telomere maintenance.

• Why it matters: Genome-wide association signals at the POLD3 locus in colorectal cancer suggest a functional mechanism, but how altered POLD3 levels affect genomic stability in CRC cells is unclear.
• What they did: Survival analyses in the Cancer Genome Atlas colon adenocarcinoma cohort used Cox proportional hazards modeling, and CRC cell lines were engineered with POLD3 knockdown to assess proliferation, S-phase arrest, DNA damage, and telomere maintenance.
• The result: POLD3 knockdown reduced proliferation and stalled S phase, with some apoptosis, while increasing DSBs and DSB repair pathway upregulation and correlating with telomere shortening via disruption of the ALT pathway.

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