PMID- 32539222
OWN - NLM
STAT- MEDLINE
DCOM- 20210301
LR  - 20210301
IS  - 1530-6860 (Electronic)
IS  - 0892-6638 (Linking)
VI  - 34
IP  - 8
DP  - 2020 Aug
TI  - Src-mediated phosphorylation of GAPDH regulates its nuclear localization and 
      cellular response to DNA damage.
PG  - 10443-10461
LID - 10.1096/fj.201902904RR [doi]
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 beta 
      (Pol beta) to function in DNA repair. Nuclear GAPDH promotes Pol beta 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.
CI  - (c) 2020 Federation of American Societies for Experimental Biology.
FAU - Ci, Shusheng
AU  - Ci S
AD  - Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life 
      Sciences, Nanjing Normal University, Nanjing, China.
FAU - Xia, Wen
AU  - Xia W
AD  - Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life 
      Sciences, Nanjing Normal University, Nanjing, China.
FAU - Liang, Weichu
AU  - Liang W
AD  - Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life 
      Sciences, Nanjing Normal University, Nanjing, China.
FAU - Qin, Lihong
AU  - Qin L
AD  - Department of Oncology, No. 7 People's Hospital of ChangZhou, Changzhou, China.
FAU - Zhang, Yilan
AU  - Zhang Y
AD  - Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life 
      Sciences, Nanjing Normal University, Nanjing, China.
FAU - Dianov, Grigory L
AU  - Dianov GL
AD  - Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life 
      Sciences, Nanjing Normal University, Nanjing, China.
AD  - Department of Natural Sciences, Novosibirsk State University, Novosibirsk, 
      Russia.
AD  - Department of Oncology, Oxford Institute for Radiation Oncology, University of 
      Oxford, Oxford, UK.
FAU - Wang, Meina
AU  - Wang M
AD  - Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life 
      Sciences, Nanjing Normal University, Nanjing, China.
FAU - Zhao, Xingqi
AU  - Zhao X
AD  - Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life 
      Sciences, Nanjing Normal University, Nanjing, China.
FAU - Wu, Congye
AU  - Wu C
AD  - Department of Oncology, Nanjing First Hospital, Nanjing Medical University, 
      Nanjing, China.
FAU - Alagamuthu, Karthick Kumar
AU  - Alagamuthu KK
AD  - Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life 
      Sciences, Nanjing Normal University, Nanjing, China.
FAU - Hu, Zhigang
AU  - Hu Z
AD  - Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life 
      Sciences, Nanjing Normal University, Nanjing, China.
FAU - He, Lingfeng
AU  - He L
AD  - Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life 
      Sciences, Nanjing Normal University, Nanjing, China.
FAU - Pan, Feiyan
AU  - Pan F
AD  - Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life 
      Sciences, Nanjing Normal University, Nanjing, China.
FAU - Guo, Zhigang
AU  - Guo Z
AD  - Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life 
      Sciences, Nanjing Normal University, Nanjing, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200615
PL  - United States
TA  - FASEB J
JT  - FASEB journal : official publication of the Federation of American Societies for 
      Experimental Biology
JID - 8804484
RN  - 9007-49-2 (DNA)
RN  - EC 1.2.1.12 (GAPDH protein, human)
RN  - EC 1.2.1.12 (Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating))
RN  - EC 2.7.10.2 (src-Family Kinases)
RN  - EC 2.7.7.7 (DNA Polymerase beta)
SB  - IM
MH  - Active Transport, Cell Nucleus/genetics
MH  - Animals
MH  - Cell Line, Tumor
MH  - Cell Nucleus/*genetics/*metabolism
MH  - Colonic Neoplasms/genetics/metabolism
MH  - DNA/genetics
MH  - DNA Damage/*genetics
MH  - DNA Polymerase beta/genetics/metabolism
MH  - DNA Repair/genetics
MH  - Female
MH  - Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)/*genetics/*metabolism
MH  - HEK293 Cells
MH  - Heterografts
MH  - Humans
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Mutation/genetics
MH  - Phosphorylation/*genetics
MH  - Protein Transport/genetics
MH  - Signal Transduction/genetics
MH  - src-Family Kinases/genetics/*metabolism
OTO - NOTNLM
OT  - DNA damage
OT  - GAPDH
OT  - Pol beta
OT  - Src
OT  - base excision repair
OT  - chemotherapy
EDAT- 2020/06/17 06:00
MHDA- 2021/03/02 06:00
CRDT- 2020/06/16 06:00
PHST- 2019/11/16 00:00 [received]
PHST- 2020/05/06 00:00 [revised]
PHST- 2020/05/22 00:00 [accepted]
PHST- 2020/06/17 06:00 [pubmed]
PHST- 2021/03/02 06:00 [medline]
PHST- 2020/06/16 06:00 [entrez]
AID - 10.1096/fj.201902904RR [doi]
PST - ppublish
SO  - FASEB J. 2020 Aug;34(8):10443-10461. doi: 10.1096/fj.201902904RR. Epub 2020 Jun 
      15.