Participation of TDP1 in the repair of formaldehyde-induced DNA-protein cross-links in chicken DT40 cells

PLoS One. 2020 Jun 26;15(6):e0234859. doi: 10.1371/journal.pone.0234859. eCollection 2020.

Abstract

Proteins are covalently trapped on DNA to form DNA-protein cross-links (DPCs) when cells are exposed to DNA-damaging agents. Aldehyde compounds produce common types of DPCs that contain proteins in an undisrupted DNA strand. Tyrosyl-DNA phosphodiesterase 1 (TDP1) repairs topoisomerase 1 (TOPO1) that is trapped at the 3'-end of DNA. In the present study, we examined the contribution of TDP1 to the repair of formaldehyde-induced DPCs using a reverse genetic strategy with chicken DT40 cells. The results obtained showed that cells deficient in TDP1 were sensitive to formaldehyde. The removal of formaldehyde-induced DPCs was slower in tdp1-deficient cells than in wild type cells. We also found that formaldehyde did not produce trapped TOPO1, indicating that trapped TOPO1 was not a primary cytotoxic DNA lesion that was generated by formaldehyde and repaired by TDP1. The formaldehyde treatment resulted in the accumulation of chromosomal breakages that were more prominent in tdp1-deficient cells than in wild type cells. Therefore, TDP1 plays a critical role in the repair of formaldehyde-induced DPCs that are distinct from trapped TOPO1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Chickens
  • Chromosome Breakage / drug effects
  • DNA / chemistry
  • DNA / metabolism*
  • DNA Breaks / drug effects
  • DNA Breaks, Double-Stranded / drug effects
  • DNA Repair*
  • DNA Topoisomerases, Type I / chemistry
  • DNA Topoisomerases, Type I / metabolism*
  • Decitabine / toxicity
  • Formaldehyde / toxicity*
  • Mitomycin / toxicity
  • Phosphoric Diester Hydrolases / genetics
  • Phosphoric Diester Hydrolases / metabolism*

Substances

  • Formaldehyde
  • Mitomycin
  • Decitabine
  • DNA
  • Phosphoric Diester Hydrolases
  • DNA Topoisomerases, Type I

Grants and funding

This work was directly supported by JSPS KAKENHI grant numbers 18K11640 to KT, 19K22561 and 16H06306 to ST, and 18H04900 and 19H04267 to HS. This work was supported by JSPS Core-to-Core Program, Advanced Research Networks to ST.