Journal article
MERIT40 Is an Akt Substrate that Promotes Resolution of DNA Damage Induced by Chemotherapy
KK Brown, L Montaser-Kouhsari, AH Beck, A Toker
Cell Reports | CELL PRESS | Published : 2015
Abstract
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 ..
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Awarded by National Institutes of Health
Funding Acknowledgements
The authors thank the histology core at the BIDMC for their technical support for IHC; Steven Elledge for providing MSCV-HA-Flag-MERIT40; Frank Sicheri for providing pLP-dmyc-TNKS2; and members of the A.T. laboratory for discussions. This work was supported in part by grants from the Department of Defense Breast Cancer Research Program (BC110900, A.T.), a John Gavin Post-doctoral Fellowship from the Genesis Oncology Trust of New Zealand (K.K.B.), and the National Library of Medicine of the NIH (K22LM011931, A.H.B).