Premium
Src‐mediated phosphorylation of GAPDH regulates its nuclear localization and cellular response to DNA damage
Author(s) -
Ci Shusheng,
Xia Wen,
Liang Weichu,
Qin Lihong,
Zhang Yilan,
Dianov Grigory L.,
Wang Meina,
Zhao Xingqi,
Wu Congye,
Alagamuthu Karthick Kumar,
Hu Zhigang,
He Lingfeng,
Pan Feiyan,
Guo Zhigang
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201902904rr
Subject(s) - glyceraldehyde 3 phosphate dehydrogenase , dna damage , dna repair , gene knockdown , biology , base excision repair , microbiology and biotechnology , proliferating cell nuclear antigen , chemistry , dna , biochemistry , dehydrogenase , enzyme , apoptosis
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.