RESUMO
BACKGROUND: Ovarian cancer patients frequently develop chemotherapy resistance, limiting treatment options. We have previously shown that individuality in fibroblast growth factor 1 (FGF1) expression influences survival and chemotherapy response. METHODS: We used MTT assays to assess chemosensitivity to cisplatin and carboplatin following shRNA-mediated knockdown or heterologous over-expression of FGF1 (quantified by qRT-PCR and immunoblot analysis), and in combination with the FGFR inhibitors AZD4547 and SU5402, the ATM inhibitor KU55933 and DNA-PK inhibitor NU7026. Immunofluorescence microscopy was used to quantify the FGF1-dependent timecourse of replication protein A (RPA) and γH2AX foci formation. RESULTS: Pharmacological inhibition of FGF signalling reversed drug resistance in immortalised cell lines and in primary cell lines from drug-resistant ovarian cancer patients, while FGF1 over-expression induced resistance. Ataxia telangiectasia mutated (ATM) phosphorylation, but not DNA adduct formation was FGF1 dependent, following cisplatin or carboplatin challenge. Combining platinum drugs with the ATM inhibitor KU55933, but not with the DNA-PK inhibitor NU7026 re-sensitised resistant cells. FGF1 expression influenced the timecourse of damage-induced RPA and γH2AX nuclear foci formation. CONCLUSION: Drug resistance arises from FGF1-mediated differential activation of high-fidelity homologous recombination DNA damage repair. FGFR and ATM inhibitors reverse platinum drug resistance, highlighting novel combination chemotherapy approaches for future clinical trial evaluation.
Assuntos
Cisplatino , Neoplasias Ovarianas , Proteínas Mutadas de Ataxia Telangiectasia , Carboplatina/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Linhagem Celular Tumoral , Cisplatino/uso terapêutico , Dano ao DNA , Reparo do DNA , Proteína Quinase Ativada por DNA/metabolismo , Resistência a Medicamentos , Feminino , Fator 1 de Crescimento de Fibroblastos/genética , Fator 1 de Crescimento de Fibroblastos/metabolismo , Fator 1 de Crescimento de Fibroblastos/uso terapêutico , Fatores de Crescimento de Fibroblastos , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Platina/uso terapêutico , RNA Interferente Pequeno , Reparo de DNA por Recombinação , Proteína de Replicação A/genéticaRESUMO
The repair of DNA double-strand breaks (DSBs) is tightly regulated during the cell cycle. In G1 phase, the absence of a sister chromatid means that repair of DSBs occurs through non-homologous end-joining or microhomology-mediated end-joining (MMEJ). These pathways often involve loss of DNA sequences at the break site and are therefore error-prone. In late S and G2 phases, even though DNA end-joining pathways remain functional, there is an increase in repair of DSBs by homologous recombination, which is mostly error-free. Consequently, the relative contribution of these different pathways to DSB repair in the cell cycle has a large influence on the maintenance of genetic integrity. It has remained unknown how DSBs are directed for repair by different, potentially competing, repair pathways. Here we identify a role for CtIP (also known as RBBP8) in this process in the avian B-cell line DT40. We establish that CtIP is required not only for repair of DSBs by homologous recombination in S/G2 phase but also for MMEJ in G1. The function of CtIP in homologous recombination, but not MMEJ, is dependent on the phosphorylation of serine residue 327 and recruitment of BRCA1. Cells expressing CtIP protein that cannot be phosphorylated at serine 327 are specifically defective in homologous recombination and have a decreased level of single-stranded DNA after DNA damage, whereas MMEJ remains unaffected. Our data support a model in which phosphorylation of serine 327 of CtIP as cells enter S phase and the recruitment of BRCA1 functions as a molecular switch to shift the balance of DSB repair from error-prone DNA end-joining to error-free homologous recombination.
Assuntos
Proteínas Aviárias/metabolismo , Proteína BRCA1/metabolismo , Proteínas de Transporte/metabolismo , Ciclo Celular , Quebras de DNA de Cadeia Dupla , Reparo do DNA/fisiologia , Proteínas Nucleares/metabolismo , Animais , Linfócitos B/citologia , Linfócitos B/metabolismo , Proteínas de Transporte/genética , Linhagem Celular , Galinhas , Cisplatino/farmacologia , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Reparo do DNA/genética , Endodesoxirribonucleases , Fase G1 , Fase G2 , Humanos , Proteínas Nucleares/genética , Fosforilação , Fosfosserina/metabolismo , Recombinação Genética/genética , Fase S , Raios XRESUMO
An important facet of transcriptional repression by Polycomb repressive complex 1 (PRC1) is the mono-ubiquitination of histone H2A by the combined action of the Posterior sex combs (Psc) and Sex combs extra (Sce) proteins. Here, we report that two ubiquitin-specific proteases, USP7 and USP11, co-purify with human PRC1-type complexes through direct interactions with the Psc orthologues MEL18 and BMI1, and with other PRC1 components. Ablation of either USP7 or USP11 in primary human fibroblasts results in de-repression of the INK4a tumour suppressor accompanied by loss of PRC1 binding at the locus and a senescence-like proliferative arrest. Mechanistically, USP7 and USP11 regulate the ubiquitination status of the Psc and Sce proteins themselves, thereby affecting their turnover and abundance. Our results point to a novel function for USPs in the regulation and function of Polycomb complexes.
Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Proteínas Repressoras/metabolismo , Tioléster Hidrolases/metabolismo , Ubiquitina Tiolesterase/metabolismo , Proliferação de Células , Células Cultivadas , Histonas/metabolismo , Humanos , Proteínas Nucleares/metabolismo , Complexo Repressor Polycomb 1 , Proteínas do Grupo Polycomb , Ligação Proteica , Proteínas Proto-Oncogênicas/metabolismo , Interferência de RNA , Tioléster Hidrolases/genética , Ubiquitina Tiolesterase/genética , Peptidase 7 Específica de Ubiquitina , UbiquitinaçãoRESUMO
BRIP1 (also called BACH1) is a DEAH helicase that interacts with the BRCT domain of BRCA1 (refs. 1-6) and has an important role in BRCA1-dependent DNA repair and checkpoint functions. We cloned the chicken ortholog of BRIP1 and established a homozygous knockout in the avian B-cell line DT40. The phenotype of these brip1 mutant cells in response to DNA damage differs from that of brca1 mutant cells and more closely resembles that of fancc mutant cells, with a profound sensitivity to the DNA-crosslinking agent cisplatin and acute cell-cycle arrest in late S-G2 phase. These defects are corrected by expression of human BRIP1 lacking the BRCT-interaction domain. Moreover, in human cells exposed to mitomycin C, short interfering RNA-mediated knock-down of BRIP1 leads to a substantial increase in chromosome aberrations, a characteristic phenotype of cells derived from individuals with Fanconi anemia. Because brip1 mutant cells are proficient for ubiquitination of FANCD2 protein, our data indicate that BRIP1 has a function in the Fanconi anemia pathway that is independent of BRCA1 and downstream of FANCD2 activation.
Assuntos
Proteína BRCA1/metabolismo , Aberrações Cromossômicas , Reparo do DNA , Anemia de Fanconi/genética , RNA Helicases/metabolismo , Transdução de Sinais , Animais , Galinhas , Cisplatino/farmacologia , Reagentes de Ligações Cruzadas/farmacologia , Dano ao DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/química , Anemia de Fanconi/metabolismo , Proteína do Grupo de Complementação D2 da Anemia de Fanconi , Proteínas de Grupos de Complementação da Anemia de Fanconi , Fase G2/efeitos dos fármacos , Células HeLa , Humanos , Mitomicina/farmacologia , Proteínas Nucleares/metabolismo , RNA Helicases/antagonistas & inibidores , RNA Helicases/química , RNA Helicases/genética , RNA Interferente Pequeno/farmacologia , Fase S/efeitos dos fármacos , Ubiquitina/metabolismoRESUMO
The protein predicted to be defective in individuals with Fanconi anemia complementation group J (FA-J), FANCJ, is a missing component in the Fanconi anemia pathway of genome maintenance. Here we identify pathogenic mutations in eight individuals with FA-J in the gene encoding the DEAH-box DNA helicase BRIP1, also called FANCJ. This finding is compelling evidence that the Fanconi anemia pathway functions through a direct physical interaction with DNA.
Assuntos
Cromossomos Humanos Par 17 , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Anemia de Fanconi/genética , Mutação/genética , RNA Helicases/deficiência , RNA Helicases/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi , Teste de Complementação Genética , Humanos , Repetições de Microssatélites , Dados de Sequência Molecular , Deleção de SequênciaRESUMO
Epigenetic dysregulation is reported in multiple cancers including Ewing sarcoma (EwS). However, the epigenetic networks underlying the maintenance of oncogenic signaling and therapeutic response remain unclear. Using a series of epigenetics- and complex-focused CRISPR screens, RUVBL1, the ATPase component of NuA4 histone acetyltransferase complex, is identified to be essential for EwS tumor progression. Suppression of RUVBL1 leads to attenuated tumor growth, loss of histone H4 acetylation, and ablated MYC signaling. Mechanistically, RUVBL1 controls MYC chromatin binding and modulates the MYC-driven EEF1A1 expression and thus protein synthesis. High-density CRISPR gene body scan pinpoints the critical MYC interacting residue in RUVBL1. Finally, this study reveals the synergism between RUVBL1 suppression and pharmacological inhibition of MYC in EwS xenografts and patient-derived samples. These results indicate that the dynamic interplay between chromatin remodelers, oncogenic transcription factors, and protein translation machinery can provide novel opportunities for combination cancer therapy.
Assuntos
Proteínas Proto-Oncogênicas c-myc , Sarcoma de Ewing , Humanos , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteína Proto-Oncogênica c-fli-1/genética , Proteína EWS de Ligação a RNA/genética , Linhagem Celular Tumoral , Transdução de Sinais/genética , Sarcoma de Ewing/genética , Cromatina , Epigênese Genética/genética , Fator 1 de Elongação de Peptídeos/genética , Fator 1 de Elongação de Peptídeos/metabolismo , Fator 1 de Elongação de Peptídeos/uso terapêutico , ATPases Associadas a Diversas Atividades Celulares/genética , ATPases Associadas a Diversas Atividades Celulares/metabolismo , Proteínas de Transporte/genética , DNA Helicases/genética , DNA Helicases/metabolismoRESUMO
Defects in the FANCJ/BRIP1 helicase gene are associated with genome instability disorders such as familial breast cancer or Fanconi anemia (FA). Although FANCJ has an in vitro activity to resolve G-quadruplex (G4) structures, and FANCJ ortholog in C. elegans prevents G4-associated deletions during replication, how FANCJ loss affects genome integrity in higher organisms remains unclear. Here, we report that FANCJ, but not other FA genes FANCD2 or FANCC, protected against large-scale genomic deletion that occurred frequently at the rearranged immunoglobulin heavy chain (IgH) locus in chicken DT40 cell line, suggesting that FancJ protects the genome independently of the FA ubiquitination pathway. In a more unbiased approach using array-comparative genomic hybridization, we identified de novo deletions as well as amplifications in fancj cells kept in culture for 2 months. A cluster of G4 sequence motifs was found near the breakpoint of one amplified region, but G4 sequence motifs were not detected at the breakpoints of two deleted regions. These results collectively suggest that, unlike in C. elegans, actions of vertebrate FANCJ to promote genome stability may not be limited to protection against the G4-mediated gene deletions.
Assuntos
Proteína do Grupo de Complementação L da Anemia de Fanconi/metabolismo , Instabilidade Genômica/genética , RNA Helicases/metabolismo , Animais , Sequência de Bases , Linhagem Celular , Galinhas , Hibridização Genômica Comparativa , Proteína do Grupo de Complementação C da Anemia de Fanconi/genética , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/genética , Proteína do Grupo de Complementação L da Anemia de Fanconi/genética , Quadruplex G , Amplificação de Genes/genética , Conversão Gênica/genética , Deleção de Genes , Ordem dos Genes , Rearranjo Gênico/genética , Marcação de Genes , Cadeias Pesadas de Imunoglobulinas/genética , Cadeias Leves de Imunoglobulina/genética , Dados de Sequência Molecular , Nucleosídeo Desaminases/genética , Nucleosídeo Desaminases/metabolismo , RNA Helicases/genética , Alinhamento de SequênciaRESUMO
Double stranded DNA Breaks (DSB) that occur in highly transcribed regions of the genome are preferentially repaired by homologous recombination repair (HR). However, the mechanisms that link transcription with HR are unknown. Here we identify a critical role for DHX9, a RNA helicase involved in the processing of pre-mRNA during transcription, in the initiation of HR. Cells that are deficient in DHX9 are impaired in the recruitment of RPA and RAD51 to sites of DNA damage and fail to repair DSB by HR. Consequently, these cells are hypersensitive to treatment with agents such as camptothecin and Olaparib that block transcription and generate DSB that specifically require HR for their repair. We show that DHX9 plays a critical role in HR by promoting the recruitment of BRCA1 to RNA as part of the RNA Polymerase II transcription complex, where it facilitates the resection of DSB. Moreover, defects in DHX9 also lead to impaired ATR-mediated damage signalling and an inability to restart DNA replication at camptothecin-induced DSB. Together, our data reveal a previously unknown role for DHX9 in the DNA Damage Response that provides a critical link between RNA, RNA Pol II and the repair of DNA damage by homologous recombination.
Assuntos
Proteína BRCA1/metabolismo , RNA Helicases DEAD-box/metabolismo , DNA , Recombinação Homóloga , Proteínas de Neoplasias/metabolismo , RNA , Proteína BRCA1/genética , RNA Helicases DEAD-box/genética , Dano ao DNA , DNA Helicases , Reparo do DNA , Replicação do DNA , Proteínas de Ligação a DNA/metabolismo , Humanos , Ftalazinas , Piperazinas , RNA Helicases , RNA Mensageiro , Rad51 Recombinase , Reparo de DNA por RecombinaçãoRESUMO
Inheritance of a mutation in BRCA1 (breast cancer 1 early-onset) results in predisposition to early-onset breast and ovarian cancer. Tumours in these individuals arise after somatic mutation or loss of the wild-type allele. Loss of BRCA1 function leads to a profound increase in genomic instability involving the accumulation of mutations, DNA breaks and gross chromosomal rearrangements. Accordingly, BRCA1 has been implicated as an important factor involved in both the repair of DNA lesions and in the regulation of cell-cycle checkpoints in response to DNA damage. However, the molecular mechanism through which BRCA1 functions to preserve genome stability remains unclear. In the present article, we examine the different ways in which BRCA1 might influence the repair of DNA damage and the preservation of genome integrity, taking into account what is currently known about its interactions with other proteins, its biochemical activity and its nuclear localization.
Assuntos
Proteína BRCA1/metabolismo , Dano ao DNA , Reparo do DNA/fisiologia , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia , Proteína BRCA1/genética , Proteína BRCA1/fisiologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular/metabolismo , Reparo do DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Chaperonas de Histonas , Histonas/metabolismo , Humanos , Modelos Biológicos , Mutação , Proteínas Nucleares/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Ligação Proteica , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/fisiologiaRESUMO
In eukaryotes, members of the phosphoinositide-3-kinase-related protein kinase (PIKK) family co-ordinate the cellular response to DNA damage. But how do these important kinases detect DNA damage and relay this information to the DNA repair and checkpoint machinery?
Assuntos
Proteínas de Ciclo Celular/metabolismo , Reparo do DNA/fisiologia , Proteínas de Ligação a DNA/metabolismo , Proteínas Nucleares/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Antígenos Nucleares/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular/genética , Quinase do Ponto de Checagem 2 , Proteínas de Ligação a DNA/genética , Exodesoxirribonucleases/metabolismo , Humanos , Autoantígeno Ku , Proteína Homóloga a MRE11 , Proteínas Nucleares/genética , Fosfoproteínas/metabolismo , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
R-loops are stable nucleic acid structures that have important physiological functions, but which also pose a significant threat to genomic stability. Increased R-loops cause replication stress and chromosome fragility and have been associated with diseases such as neurodegeneration and cancer. Although excessive R-loops are a feature of cells that are defective in RNA processing, what causes them to form is unclear. Here, we demonstrate that DHX9 (RNA helicase A) promotes the formation of pathological and non-pathological R-loops. In the absence of splicing factors, formation of R-loops correlates with the prolonged association of DHX9 with RNA Polymerase II (RNA Pol II). This leads to the production of DNA-RNA hybrid, which traps RNA Pol II on chromatin with the potential to block DNA replication. Our data provide a molecular mechanism for the formation of R-loops that is relevant to neurodegenerative diseases and cancers in which deregulated RNA processing is a feature.
Assuntos
RNA Helicases DEAD-box/fisiologia , Modelos Moleculares , Proteínas de Neoplasias/fisiologia , Splicing de RNA/fisiologia , RNA Helicases DEAD-box/química , Replicação do DNA/fisiologia , Instabilidade Genômica , Células HeLa , Humanos , Proteínas de Neoplasias/química , Conformação de Ácido Nucleico , RNA Polimerase II/química , RNA Polimerase II/metabolismo , RNA Polimerase II/fisiologia , Fatores de Processamento de RNA/química , Fatores de Processamento de RNA/metabolismoRESUMO
In higher organisms, a major pathway for repairing double stranded breaks in DNA is non-homologous end-joining. Now a similar pathway has been shown to operate in bacterial cells, indicating that this important repair mechanism has been conserved through evolution.
Assuntos
Bactérias/genética , DNA Helicases , Reparo do DNA/fisiologia , Animais , Antígenos Nucleares/fisiologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , DNA Ligase Dependente de ATP , DNA Ligases/genética , DNA Ligases/metabolismo , Proteínas de Ligação a DNA/fisiologia , Autoantígeno Ku , Mamíferos/genéticaRESUMO
The Fanconi anemia DNA repair pathway is pivotal for the efficient repair of DNA interstrand cross-links. Here, we show that FA-defective (Fancc(-)) DT40 cells arrest in G2 phase following cross-link damage and trigger apoptosis. Strikingly, cell death was reduced in Fancc(-) cells by additional deletion of the BRCA1 tumor suppressor, resulting in elevated clonogenic survival. Increased resistance to cross-link damage was not due to loss of toxic BRCA1-mediated homologous recombination but rather through the loss of a G2 checkpoint. This proapoptotic role also required the BRCA1-A complex member ABRAXAS (FAM175A). Finally, we show that BRCA1 promotes G2 arrest and cell death by prolonging phosphorylation of Chk1 on serine 345 after DNA damage to sustain arrest. Our data imply that DNA-induced cross-link death in cells defective in the FA pathway is dependent on the ability of BRCA1 to prolong cell cycle arrest in G2 phase.
Assuntos
Proteínas Aviárias/metabolismo , Proteína BRCA1/metabolismo , Reparo do DNA , Pontos de Checagem da Fase G2 do Ciclo Celular , Proteínas Quinases/metabolismo , Animais , Apoptose , Proteínas Aviárias/genética , Proteína BRCA1/genética , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular , Quinase 1 do Ponto de Checagem , Galinhas , Anemia de Fanconi/genética , Anemia de Fanconi/metabolismo , Proteína do Grupo de Complementação C da Anemia de Fanconi/genética , Proteína do Grupo de Complementação C da Anemia de Fanconi/metabolismo , Deleção de Genes , FosforilaçãoRESUMO
A new study identifies rare mutations in SPRTN that cause a novel progeroid syndrome. The results point to an unexpected function of SPRTN and bring insight to the mechanisms that link premature aging and cancer.
Assuntos
Carcinoma Hepatocelular/genética , Proteínas de Ligação a DNA/genética , Instabilidade Genômica/genética , Neoplasias Hepáticas/genética , Progéria/genética , Animais , Humanos , MasculinoRESUMO
The RING domain proteins BRCA1 and BARD1 comprise a heterodimeric ubiquitin (E3) ligase that is required for the accumulation of ubiquitin conjugates at sites of DNA damage and for silencing at DNA satellite repeat regions. Despite its links to chromatin, the substrate and underlying function of the BRCA1/BARD1 ubiquitin ligase remain unclear. Here, we show that BRCA1/BARD1 specifically ubiquitylates histone H2A in its C-terminal tail on lysines 127 and 129 in vitro and in vivo. The specificity for K127-129 is acquired only when H2A is within a nucleosomal context. Moreover, site-specific targeting of the BRCA1/BARD1 RING domains to chromatin is sufficient for H2Aub foci formation in vivo. Our data establish BRCA1/BARD1 as a histone-H2A-specific E3 ligase, helping to explain its localization and activities on chromatin in cells.
Assuntos
Proteína BRCA1/fisiologia , Histonas/metabolismo , Ubiquitina-Proteína Ligases/fisiologia , Ubiquitinação , Sequência de Aminoácidos , Animais , Domínio Catalítico , Galinhas , Células HEK293 , Células HeLa , Humanos , Dados de Sequência Molecular , Nucleossomos/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Xenopus laevisRESUMO
How do two identical DNA sequences find each other during homologous recombination, amidst a 'sea' of unrelated DNA? New studies reveal how RecA promotes the search for homology by sampling DNA in three dimensions.
Assuntos
Recombinação Homóloga , Recombinases Rec A/metabolismo , Homologia de Sequência do Ácido Nucleico , DNARESUMO
The FANCJ protein (also known as BACH1 and BRIP1) is a DNA helicase that is required to preserve the genetic and structural integrity of the genome in complex eukaryotes. In humans, mutations in FANCJ are associated with the chromosome instability disorder Fanconi's anemia and also with the inherited predisposition early-onset breast cancer. Here I will discuss the contribution of FANCJ to human disease, its role in maintenance of genome stability and some current thoughts on the mechanisms through which this is achieved.
Assuntos
DNA Helicases/metabolismo , Replicação do DNA , Animais , Anemia de Fanconi/enzimologia , Proteínas de Grupos de Complementação da Anemia de Fanconi , Instabilidade Genômica , Humanos , Neoplasias/enzimologiaRESUMO
The repair of DNA double strand breaks (dsb) is important for maintaining the physical and genetic integrity of the genome. Moreover, in humans it is associated with the prevention of diseases such as immune deficiencies and cancer. This review briefly explores the fundamental strategies for repairing dsb, examines how cells maximize the fidelity of dsb repair in the cell cycle and discusses the requirements for dsb repair in the context of chromatin.
Assuntos
Ciclo Celular/fisiologia , Cromatina/fisiologia , Quebras de DNA de Cadeia Dupla , Reparo do DNA/fisiologia , Instabilidade Genômica/genética , Recombinação Genética/fisiologia , Cromatina/genética , Reparo do DNA/genética , Humanos , Recombinação Genética/genéticaRESUMO
In bacteria, the RecF pathway plays an important role in the repair of DNA breaks and gaps. Reconstitution of this reaction in vitro has revealed similarities with double-strand break repair in eukaryotes.
Assuntos
Quebras de DNA de Cadeia Dupla , Reparo do DNA , DNA Bacteriano , DNA Bacteriano/genética , DNA Bacteriano/metabolismo , Proteínas de Ligação a DNA/metabolismo , Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , HumanosRESUMO
Ubiquitin is known to accumulate at the sites of DNA damage. The identification of a new ubiquitin ligase, RIDDLIN, provides evidence for a ubiquitin-signalling cascade that regulates the assembly of an important DNA repair complex at a DNA double-strand break.