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1.
Nat Commun ; 13(1): 957, 2022 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-35177609

RESUMO

The 53BP1-RIF1 pathway antagonizes resection of DNA broken ends and confers PARP inhibitor sensitivity on BRCA1-mutated tumors. However, it is unclear how this pathway suppresses initiation of resection. Here, we identify ASF1 as a partner of RIF1 via an interacting manner similar to its interactions with histone chaperones CAF-1 and HIRA. ASF1 is recruited to distal chromatin flanking DNA breaks by 53BP1-RIF1 and promotes non-homologous end joining (NHEJ) using its histone chaperone activity. Epistasis analysis shows that ASF1 acts in the same NHEJ pathway as RIF1, but via a parallel pathway with the shieldin complex, which suppresses resection after initiation. Moreover, defects in end resection and homologous recombination (HR) in BRCA1-deficient cells are largely suppressed by ASF1 deficiency. Mechanistically, ASF1 compacts adjacent chromatin by heterochromatinization to protect broken DNA ends from BRCA1-mediated resection. Taken together, our findings identify a RIF1-ASF1 histone chaperone complex that promotes changes in high-order chromatin structure to stimulate the NHEJ pathway for DSB repair.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Cromatina/metabolismo , Reparo do DNA por Junção de Extremidades , Chaperonas Moleculares/metabolismo , Proteínas de Ligação a Telômeros/metabolismo , Animais , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteínas de Ciclo Celular/genética , Linhagem Celular Tumoral , Galinhas , Cromatina/genética , Epistasia Genética , Técnicas de Silenciamento de Genes , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Chaperonas Moleculares/genética , Proteínas de Ligação a Telômeros/genética
2.
Polymers (Basel) ; 13(4)2021 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-33672921

RESUMO

Polyurethane has a microphase separation structure, while polyethylene glycol (PEG) can form a hydrated layer to resist protein adsorption. In this paper, PEG was introduced to polyurethane to improve the antifouling properties of the polyurethane, providing a new method and idea for the preparation of new antifouling polyurethane materials. The mechanical properties, hydrophilicity, swelling degree, microphase separation and antifouling performance of the coatings were evaluated. The response characteristics of the polyurethane coatings in a seawater environment were studied, and the performance changes of coatings in seawater were tested. The results showed that the crystallized PEG soft segments increased, promoting microphase separation. The stress at 100% and the elasticity modulus of the polyurethane material also markedly increased, in addition to increases in the swelling degree in seawater, the water contact angle decreased. A total of 25% of PEG incorporated into a soft segment can markedly improve the antibacterial properties of the coatings, but adding more PEG has little significant effect. After immersion in seawater, the coatings became softer and more elastic. This is because water molecules formed hydrogen bonding with the amino NH, which resulted in a weakening effect being exerted on the carbonyl C=O hydrogen bonding and ether oxygen group crystallization.

3.
Cell ; 182(2): 481-496.e21, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32649862

RESUMO

The response to DNA damage is critical for cellular homeostasis, tumor suppression, immunity, and gametogenesis. In order to provide an unbiased and global view of the DNA damage response in human cells, we undertook 31 CRISPR-Cas9 screens against 27 genotoxic agents in the retinal pigment epithelium-1 (RPE1) cell line. These screens identified 890 genes whose loss causes either sensitivity or resistance to DNA-damaging agents. Mining this dataset, we discovered that ERCC6L2 (which is mutated in a bone-marrow failure syndrome) codes for a canonical non-homologous end-joining pathway factor, that the RNA polymerase II component ELOF1 modulates the response to transcription-blocking agents, and that the cytotoxicity of the G-quadruplex ligand pyridostatin involves trapping topoisomerase II on DNA. This map of the DNA damage response provides a rich resource to study this fundamental cellular system and has implications for the development and use of genotoxic agents in cancer therapy.


Assuntos
Dano ao DNA , Redes Reguladoras de Genes/fisiologia , Aminoquinolinas/farmacologia , Animais , Sistemas CRISPR-Cas/genética , Linhagem Celular , Citocromo-B(5) Redutase/genética , Citocromo-B(5) Redutase/metabolismo , Dano ao DNA/efeitos dos fármacos , DNA Helicases/genética , DNA Helicases/metabolismo , Reparo do DNA , DNA Topoisomerases Tipo II/genética , DNA Topoisomerases Tipo II/metabolismo , Humanos , Camundongos , Ácidos Picolínicos/farmacologia , RNA Guia de Cinetoplastídeos/metabolismo , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genética
4.
Nat Commun ; 9(1): 3925, 2018 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-30254264

RESUMO

53BP1 with its downstream proteins, RIF1, PTIP and REV7, antagonizes BRCA1-dependent homologous recombination (HR) and promotes non-homologous end joining (NHEJ) in an unclear manner. Here we show that REV7 forms a complex with two proteins, FAM35A and C20ORF196. We demonstrate that FAM35A preferentially binds single-strand DNA (ssDNA) in vitro, and is recruited to DSBs as a complex with C20ORF196 and REV7 downstream of RIF1 in vivo. Epistasis analysis shows that both proteins act in the same pathway as RIF1 in NHEJ. The defects in HR pathway to repair DSBs and the reduction in resection of broken DNA ends in BRCA1-mutant cells can be largely suppressed by inactivating FAM35A or C20ORF196, indicating that FAM35A and C20ORF196 prevent end resection in these cells. Together, our data identified a REV7-FAM35A-C20ORF196 complex that binds and protects broken DNA ends to promote the NHEJ pathway for DSB repair.


Assuntos
Quebras de DNA de Cadeia Dupla , Reparo do DNA por Junção de Extremidades , Complexos Multiproteicos/metabolismo , Transdução de Sinais , Animais , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Proteínas de Ligação a DNA , Células HCT116 , Recombinação Homóloga , Humanos , Proteínas Mad2/genética , Proteínas Mad2/metabolismo , Complexos Multiproteicos/genética , Proteínas/genética , Proteínas/metabolismo , Interferência de RNA , Proteínas de Ligação a Telômeros/genética , Proteínas de Ligação a Telômeros/metabolismo , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/genética , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo
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