Src-mediated phosphorylation of GAPDH regulates its nuclear localization and cellular response to DNA damage

Shusheng Ci, Wen Xia, Weichu Liang, Lihong Qin, Yilan Zhang, Grigory L. Dianov, Meina Wang, Xingqi Zhao, Congye Wu, Karthick Kumar Alagamuthu, Zhigang Hu, Lingfeng He, Feiyan Pan, Zhigang Guo

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key enzyme involved in energy metabolism. Recently, GAPDH has been suggested to have extraglycolytic functions in DNA repair, but the underlying mechanism for the GAPDH response to DNA damage remains unclear. Here, we demonstrate that the tyrosine kinase Src is activated under DNA damage stress and phosphorylates GAPDH at Tyr41. This phosphorylation of GAPDH is essential for its nuclear translocation and DNA repair function. Blocking the nuclear import of GAPDH by suppressing Src signaling or through a GAPDH Tyr41 mutation impairs its response to DNA damage. Nuclear GAPDH is recruited to DNA lesions and associates with DNA polymerase β (Pol β) to function in DNA repair. Nuclear GAPDH promotes Pol β polymerase activity and increases base excision repair (BER) efficiency. Furthermore, GAPDH knockdown dramatically decreases BER efficiency and sensitizes cells to DNA damaging agents. Importantly, the knockdown of GAPDH in colon cancer SW480 cells and xenograft models effectively enhances their sensitivity to the chemotherapeutic drug 5-FU. In summary, our findings provide mechanistic insight into the new function of GAPDH in DNA repair and suggest a potential therapeutic target in chemotherapy.

Original languageEnglish
Pages (from-to)10443-10461
Number of pages19
JournalFASEB Journal
Volume34
Issue number8
Early online date15 Jun 2020
DOIs
Publication statusPublished - 1 Aug 2020

Keywords

  • base excision repair
  • chemotherapy
  • DNA damage
  • GAPDH
  • Pol β
  • Src
  • ACTIVATION
  • PROTEIN
  • BETA-GENE MUTATION
  • KINASE
  • POLYMERASE-BETA
  • Pol beta
  • CANCER
  • BASE EXCISION-REPAIR
  • RESISTANCE
  • EXPRESSION
  • HUMAN GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE

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