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SMYD3 Modulates AMPK-mTOR Signaling Balance in Cancer Cell Response to DNA Damage

Martina Lepore Signorile1, Paola Sanese1, Elisabetta Di Nicola1

  • 1Medical Genetics, National Institute of Gastroenterology-IRCCS "Saverio de Bellis" Research Hospital, 70013 Castellana Grotte, Italy.

Cells
|November 24, 2023
PubMed

Insights

The study reveals SMYD3

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • Cells activate complex signaling networks, including AMPK and mTOR pathways, in response to DNA damage.
  • ATM kinase initiates the AMPK-TSC2 pathway, inhibiting mTOR cascade following DNA double-strand breaks.
  • SMYD3, a methyltransferase, has been identified to interact with both AMPK and mTOR in DNA damage response.

Purpose of the Study:

  • To investigate the role of SMYD3 in the multiprotein complex involving AMPK and mTOR during DNA damage response.
  • To elucidate the mechanism by which SMYD3 modulates the AMPK-mTOR signaling balance in cancer cells.
  • To determine if SMYD3 directly modifies AMPK activity through methylation.

Main Methods:

  • Extensive molecular characterization of gastrointestinal and breast cancer cells.
  • Pharmacological inhibition of SMYD3 activity.
  • Analysis of AMPK and mTOR pathway activation.
  • Methylation site analysis of AMPK by SMYD3.

Main Results:

  • SMYD3 forms a multiprotein complex with AMPK and mTOR involved in DNA damage response.
  • SMYD3 inhibition suppresses AMPK activation and promotes the mTOR pathway upon DNA double-strand breaks.
  • SMYD3 methylates AMPK at evolutionarily conserved residues Lys411 and Lys424.

Conclusions:

  • SMYD3 plays a central role in balancing AMPK-mTOR signaling during cancer cell response to DNA double-strand breaks.
  • SMYD3 acts as a molecular bridge connecting the AMPK and mTOR pathways following DNA damage.
  • SMYD3-mediated methylation of AMPK is a key mechanism in this signaling crosstalk.
Keywords:
AMPKDNA damageSMYD3breast cancergastrointestinal cancermTOR

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