Research output: Contribution to journal › Article › peer-review
Src-mediated phosphorylation of GAPDH regulates its nuclear localization and cellular response to DNA damage. / Ci, Shusheng; Xia, Wen; Liang, Weichu et al.
In: FASEB Journal, Vol. 34, No. 8, 01.08.2020, p. 10443-10461.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Src-mediated phosphorylation of GAPDH regulates its nuclear localization and cellular response to DNA damage
AU - Ci, Shusheng
AU - Xia, Wen
AU - Liang, Weichu
AU - Qin, Lihong
AU - Zhang, Yilan
AU - Dianov, Grigory L.
AU - Wang, Meina
AU - Zhao, Xingqi
AU - Wu, Congye
AU - Alagamuthu, Karthick Kumar
AU - Hu, Zhigang
AU - He, Lingfeng
AU - Pan, Feiyan
AU - Guo, Zhigang
N1 - Publisher Copyright: © 2020 Federation of American Societies for Experimental Biology Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - 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.
AB - 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.
KW - base excision repair
KW - chemotherapy
KW - DNA damage
KW - GAPDH
KW - Pol β
KW - Src
KW - ACTIVATION
KW - PROTEIN
KW - BETA-GENE MUTATION
KW - KINASE
KW - POLYMERASE-BETA
KW - Pol beta
KW - CANCER
KW - BASE EXCISION-REPAIR
KW - RESISTANCE
KW - EXPRESSION
KW - HUMAN GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE
UR - http://www.scopus.com/inward/record.url?scp=85086446829&partnerID=8YFLogxK
U2 - 10.1096/fj.201902904RR
DO - 10.1096/fj.201902904RR
M3 - Article
C2 - 32539222
AN - SCOPUS:85086446829
VL - 34
SP - 10443
EP - 10461
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 8
ER -
ID: 24517728