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ERK3 regulates TDP2-mediated DNA damage response and chemoresistance in lung cancer cells

Ka Bian1, Naveen Reddy Muppani2, Lobna Elkhadragy2

  • 1Department of Otorhinolaryngology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.

Oncotarget
|December 25, 2015
PubMed

Insights

This study reveals that ERK3 phosphorylates Tyrosyl DNA phosphodiesterase 2 (TDP2), enhancing its activity. This interaction protects lung cancer cells from DNA damage and promotes chemoresistance to Topoisomerase 2 inhibitors.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Biochemistry

Background:

  • Posttranslational modifications (PTMs) regulate DNA damage response (DDR) proteins.
  • Tyrosyl DNA phosphodiesterase 2 (TDP2) repairs Topoisomerase 2 (Top2)-linked DNA damage, crucial for cancer cell survival under Top2 inhibitor treatment.
  • Mechanisms of TDP2 regulation by PTMs in DNA repair are not fully understood.

Purpose of the Study:

  • To investigate the posttranslational regulation of TDP2 activity.
  • To identify novel regulators of TDP2 involved in DNA damage repair and chemoresistance.

Main Methods:

  • Western blotting and immunoprecipitation to detect protein interactions and phosphorylation.
  • Enzyme activity assays to measure TDP2 phosphodiesterase activity.
  • Cell viability assays to assess the impact of ERK3 and TDP2 on lung cancer cell response to Top2 inhibitors.

Main Results:

  • Extracellular signal-regulated kinase 3 (ERK3), an atypical MAPK, was identified as a kinase that phosphorylates TDP2 at serine 60 (S60).
  • Phosphorylation of TDP2 by ERK3 enhances TDP2's phosphodiesterase activity.
  • ERK3 and TDP2 cooperatively protect lung cancer cells against Top2 inhibitors-induced DNA damage and growth inhibition, increasing chemoresistance.

Conclusions:

  • ERK3-mediated phosphorylation of TDP2 is a novel mechanism regulating TDP2 activity in DNA repair.
  • ERK3 plays a significant role in enhancing cancer cells' DNA damage response and chemoresistance to Top2 inhibitors.
  • This finding reveals a new therapeutic target for overcoming resistance to Top2 inhibitor chemotherapy in lung cancer.
Keywords:
DNA damageERK3TDP2Top2 inhibitorschemoresistance

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