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Non-transcriptional Function of FOXO1/DAF-16 Contributes to Translesion DNA Synthesis

Hiroaki Daitoku1, Yuta Kaneko2, Kenji Yoshimochi2

  • 1Life Science Center, Tsukuba Advanced Research Alliance Graduate School of Life and Environmental Sciences , University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki, Japan.

Molecular and Cellular Biology
|August 24, 2016
PubMed

Insights

Forkhead box O (FOXO) proteins, particularly FOXO1, play a crucial role in repairing UV-induced DNA damage through translesion DNA synthesis (TLS). This function is independent of FOXO

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • Forkhead box O (FOXO) transcription factors regulate stress resistance, metabolism, and lifespan.
  • Stochastic DNA damage significantly impacts organismal development and aging.
  • The role of FOXO/DAF-16 in DNA damage response, specifically UV-induced damage, requires further investigation.

Purpose of the Study:

  • To investigate the role of FOXO/DAF-16 transcription factors in the cellular response to UV-induced DNA damage.
  • To determine the specific FOXO1 contribution to translesion DNA synthesis (TLS) in response to UV irradiation.
  • To elucidate the mechanism by which FOXO1 participates in DNA repair pathways.

Main Methods:

  • Utilized knockdown of FOXO1 and FOXO3a in mammalian cells to assess UV sensitivity during S phase.
  • Analyzed ATR-Chk1 signaling pathway activation and PCNA monoubiquitination following UV irradiation in FOXO1-depleted cells.
  • Investigated FOXO1 binding to Replication Protein A (RPA1) using biochemical assays.
  • Examined UV-induced developmental retardation in Caenorhabditis elegans daf-16 null mutants and rescue experiments with DAF-16 variants.

Main Results:

  • FOXO1 knockdown, but not FOXO3a, increased sensitivity to UV irradiation during S phase, indicating a role in TLS.
  • FOXO1 depletion led to sustained ATR-Chk1 signaling activation and reduced PCNA monoubiquitination post-UV.
  • FOXO1 was found to bind to RPA1, a key component of the TLS machinery, without altering TLS gene expression.
  • C. elegans daf-16 null mutants exhibited UV-induced developmental delays, which were rescued by a DAF-16 variant lacking its transactivation domain but not one unable to bind RPA1.

Conclusions:

  • FOXO1 is a functional component of the translesion DNA synthesis (TLS) pathway, crucial for repairing UV-induced DNA lesions.
  • The DNA repair function of FOXO1/DAF-16 in TLS is independent of its transcriptional activation activity.
  • FOXO1 interacts with RPA1, suggesting a scaffold or regulatory role in the TLS process, distinct from its canonical gene regulation functions.

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