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1.
EMBO Rep ; 24(8): e56437, 2023 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-37306047

RESUMO

Homologous recombination (HR), a form of error-free DNA double-strand break (DSB) repair, is important for the maintenance of genomic integrity. Here, we identify a moonlighting protein, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), as a regulator of HR repair, which is mediated through HDAC1-dependent regulation of RAD51 stability. Mechanistically, in response to DSBs, Src signaling is activated and mediates GAPDH nuclear translocation. Then, GAPDH directly binds with HDAC1, releasing it from its suppressor. Subsequently, activated HDAC1 deacetylates RAD51 and prevents it from undergoing proteasomal degradation. GAPDH knockdown decreases RAD51 protein levels and inhibits HR, which is re-established by overexpression of HDAC1 but not SIRT1. Notably, K40 is an important acetylation site of RAD51, which facilitates stability maintenance. Collectively, our findings provide new insights into the importance of GAPDH in HR repair, in addition to its glycolytic activity, and they show that GAPDH stabilizes RAD51 by interacting with HDAC1 and promoting HDAC1 deacetylation of RAD51.


Assuntos
Reparo do DNA , Reparo de DNA por Recombinação , Recombinação Homóloga , Quebras de DNA de Cadeia Dupla , Rad51 Recombinase/genética , Rad51 Recombinase/metabolismo
2.
Int J Mol Sci ; 24(3)2023 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-36768821

RESUMO

Short-term starvation (STS) during chemotherapy can block the nutrient supply to tumors and make tumor cells much more sensitive to chemotherapeutic drugs than normal cells. However, because of the diversity of starvation methods and the heterogeneity of tumors, this method's specific effects and mechanisms for chemotherapy are still poorly understood. In this study, we used HeLa cells as a model for short-term starvation and etoposide (ETO) combined treatment, and we also mimicked the short-term starvation effect by knocking down the glycolytic enzyme GAPDH to explore the exact molecular mechanism. In addition, our study demonstrated that short-term starvation protects cancer cells against the chemotherapeutic agent ETO by reducing DNA damage and apoptosis due to the STS-induced cell cycle G1 phase block and S phase reduction, thereby diminishing the effect of ETO. Furthermore, these results suggest that starvation therapy in combination with cell cycle-specific chemotherapeutic agents must be carefully considered.


Assuntos
Apoptose , Inanição , Humanos , Células HeLa , Ciclo Celular , Divisão Celular , Etoposídeo/farmacologia , Fase G1
3.
Free Radic Biol Med ; 164: 175-186, 2021 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-33418111

RESUMO

It has been established that 8-oxoguanine DNA glycosylase 1 (OGG1) is the main enzyme removing oxidized guanine under oxidative stress. However, increasing evidence has shown that OGG1 is not only a base excision repair protein but also a new transcriptional coactivator involved in oxidative stress-induced gene expression. Its downstream target genes and the underlying regulatory mechanisms still need to be discerned. Here, it was discovered that c-Myc is a downstream target of OGG1 under oxidative stress and that H4R3me2a is involved in this transcriptional regulation. The increased level of H4R3me2a induced by H2O2 is regulated by OGG1, which may directly interact with the specific arginine methyltransferase PRMT1 and promote the asymmetrical dimethylation of H4R3me1. H4R3me2a enrichment on the promoter of c-Myc can recruit YY1 and activate c-Myc transcription. Moreover, knocking down OGG1 or PRMT1 suppresses c-Myc transcription under oxidative stress by downregulating H4R3me2a formation. Furthermore, the overexpression of wild type (WT) H4R3 promotes c-Myc transcription, but the expression of mutant H4R3Q does not have this effect. Taken together, our data show that the 8-oxoG/OGG1/PRMT1/H4R3me2a/YY1 axis senses oxidative stress and promotes gene transcription.


Assuntos
DNA Glicosilases , Histonas , Animais , Arginina , Linhagem Celular , DNA Glicosilases/genética , DNA Glicosilases/metabolismo , Reparo do DNA , Guanina/análogos & derivados , Histonas/genética , Histonas/metabolismo , Humanos , Peróxido de Hidrogênio/farmacologia , Camundongos , Estresse Oxidativo/genética , Proteína-Arginina N-Metiltransferases , Proteínas Repressoras , Ativação Transcricional
4.
FASEB J ; 34(8): 10443-10461, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32539222

RESUMO

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 ß (Pol ß) to function in DNA repair. Nuclear GAPDH promotes Pol ß 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.


Assuntos
Núcleo Celular/genética , Núcleo Celular/metabolismo , Dano ao DNA/genética , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/genética , Gliceraldeído-3-Fosfato Desidrogenase (Fosforiladora)/metabolismo , Fosforilação/genética , Quinases da Família src/metabolismo , Transporte Ativo do Núcleo Celular/genética , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , DNA/genética , DNA Polimerase beta/genética , DNA Polimerase beta/metabolismo , Reparo do DNA/genética , Feminino , Células HEK293 , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mutação/genética , Transporte Proteico/genética , Transdução de Sinais/genética , Quinases da Família src/genética
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