Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) interacts with apurinic/apyrimidinic sites in DNA

Kosova, Anastasiya A.; Ходырева, С. Н.; Lavrik, Olga I.

doi:10.1016/j.mrfmmm.2015.06.005

Cited by 21 publications

(16 citation statements)

References 58 publications

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“…Our data showed that MMS triggered more GAPDH binding to the AP-containing DNA ( Figure 1C), which is consistent with the previous study. 16 Taken together, our data showed that in response to DNA damage GAPDH translocates into the nucleus and localizes to the damaged sites.…”

Section: Gapdh Translocates Into the Nucleus And Localizes To The Dsupporting

confidence: 60%

“…Studies have confirmed that GAPDH could bind to DNA containing Apurinic/apyrimidinic (AP) sites. 16 GAPDH was also found to interact with the DNA repair protein apurinic endonuclease 1 (APE1) 17 and regulate APE1 expression. 18 However, although these findings suggest that GAPDH plays an important role in DNA repair, how GAPDH translocates to the nucleus in response to DNA damage and how it functions in DNA repair remains largely unknown.…”

Section: Introductionmentioning

confidence: 99%

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

Wen

Liang

et al. 2020

The FASEB Journal

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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.

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Section: Gapdh Translocates Into the Nucleus And Localizes To The Dsupporting

confidence: 60%

Section: Introductionmentioning

confidence: 99%

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

Wen

Liang

et al. 2020

The FASEB Journal

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“…More recently, direct interaction of GAPDH was evidenced with apyrimidic/apuric (AP) sites in double stranded DNA. The AP site recognition was followed by a stable crosslink via β-elimination to form an adduct through thiol oxidation of GAPDH without AP lyase activity to further remove AP site and generate a strand break [ 182 ].…”

Section: Glyceraldehyde-3-phosphate Dehydrogenase (Gapdh) Binding mentioning

confidence: 99%

“…Similarly stress-induced DNA damage results in an increased level of polyphosphate diadenine (Ap4A) that is then recognized by PARP [ 190 ], but also by GAPDH/UDG in HeLa cells [ 191 ]. As indicated above, direct covalent interaction of GAPDH with AP site was very recently evidenced that could participate in DNA repair process maybe as a damage sensor or damage protection mechanism that needs to be further investigate [ 182 ].…”

Section: Glyceraldehyde-3-phosphate Dehydrogenase (Gapdh) Binding mentioning

confidence: 99%

Protein Recognition in Drug-Induced DNA Alkylation: When the Moonlight Protein GAPDH Meets S23906-1/DNA Minor Groove Adducts

Savreux-Lenglet

Depauw

David-Cordonnier

2015

IJMS

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DNA alkylating drugs have been used in clinics for more than seventy years. The diversity of their mechanism of action (major/minor groove; mono-/bis-alkylation; intra-/inter-strand crosslinks; DNA stabilization/destabilization, etc.) has undoubtedly major consequences on the cellular response to treatment. The aim of this review is to highlight the variety of established protein recognition of DNA adducts to then particularly focus on glyceraldehyde-3-phosphate dehydrogenase (GAPDH) function in DNA adduct interaction with illustration using original experiments performed with S23906-1/DNA adduct. The introduction of this review is a state of the art of protein/DNA adducts recognition, depending on the major or minor groove orientation of the DNA bonding as well as on the molecular consequences in terms of double-stranded DNA maintenance. It reviews the implication of proteins from both DNA repair, transcription, replication and chromatin maintenance in selective DNA adduct recognition. The main section of the manuscript is focusing on the implication of the moonlighting protein GAPDH in DNA adduct recognition with the model of the peculiar DNA minor groove alkylating and destabilizing drug S23906-1. The mechanism of action of S23906-1 alkylating drug and the large variety of GAPDH cellular functions are presented prior to focus on GAPDH direct binding to S23906-1 adducts.

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“…Mammalian glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and cyclin O (CCNO) have also been reported to have uracil excision activity ( 203 – 205 ). These activities have not been characterized beyond these initial reports, though a 2015 study reported that while GAPDH binds strongly to abasic sites, no uracil excision activity was observed ( 206 ). Note that there was some initial confusion in the literature between CCNO and the nuclear UNG isoform UNG2; CCNO was originally named UDG2, which led some early studies of UNG2 to conflate the two proteins.…”

Section: Base Damage Repair Pathwaysmentioning

confidence: 99%

The current state of eukaryotic DNA base damage and repair

2015

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DNA damage is a natural hazard of life. The most common DNA lesions are base, sugar, and single-strand break damage resulting from oxidation, alkylation, deamination, and spontaneous hydrolysis. If left unrepaired, such lesions can become fixed in the genome as permanent mutations. Thus, evolution has led to the creation of several highly conserved, partially redundant pathways to repair or mitigate the effects of DNA base damage. The biochemical mechanisms of these pathways have been well characterized and the impact of this work was recently highlighted by the selection of Tomas Lindahl, Aziz Sancar and Paul Modrich as the recipients of the 2015 Nobel Prize in Chemistry for their seminal work in defining DNA repair pathways. However, how these repair pathways are regulated and interconnected is still being elucidated. This review focuses on the classical base excision repair and strand incision pathways in eukaryotes, considering both Saccharomyces cerevisiae and humans, and extends to some important questions and challenges facing the field of DNA base damage repair.

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Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) interacts with apurinic/apyrimidinic sites in DNA

Cited by 21 publications

References 58 publications

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

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

Protein Recognition in Drug-Induced DNA Alkylation: When the Moonlight Protein GAPDH Meets S23906-1/DNA Minor Groove Adducts

The current state of eukaryotic DNA base damage and repair

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