MERIT40 Is an Akt Substrate that Promotes Resolution of DNA Damage Induced by Chemotherapy

Cell Rep. 2015 Jun 9;11(9):1358-66. doi: 10.1016/j.celrep.2015.05.004. Epub 2015 May 28.


Resistance to cytotoxic chemotherapy drugs, including doxorubicin, is a significant obstacle to the effective treatment of breast cancer. Here, we have identified a mechanism by which the PI3K/Akt pathway mediates resistance to doxorubicin. In addition to inducing DNA damage, doxorubicin triggers sustained activation of Akt signaling in breast cancer cells. We show that Akt contributes to chemotherapy resistance such that PI3K or Akt inhibitors sensitize cells to doxorubicin. We identify MERIT40, a component of the BRCA1-A DNA damage repair complex, as an Akt substrate that is phosphorylated following doxorubicin treatment. MERIT40 phosphorylation facilitates assembly of the BRCA1-A complex in response to DNA damage and contributes to DNA repair and cell survival following doxorubicin treatment. Finally, MERIT40 phosphorylation in human breast cancers is associated with estrogen receptor positivity. Our findings suggest that combination therapy with PI3K or Akt inhibitors and doxorubicin may constitute a successful strategy for overcoming chemotherapy resistance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Antineoplastic Agents / pharmacology
  • Breast Neoplasms*
  • Cell Line, Tumor
  • DNA Damage / drug effects*
  • DNA Repair / drug effects
  • Doxorubicin / pharmacology
  • Drug Resistance, Neoplasm / physiology*
  • Enzyme Inhibitors / pharmacology
  • Female
  • Fluorescent Antibody Technique
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Tissue Array Analysis


  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • BABAM1 protein, human
  • Enzyme Inhibitors
  • Doxorubicin
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt