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1.
Genes Dev ; 34(21-22): 1520-1533, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-33060134

RESUMO

DNA replication is fundamental for cell proliferation in all organisms. Nonetheless, components of the replisome have been implicated in human disease, and here we report PRIM1 encoding the catalytic subunit of DNA primase as a novel disease gene. Using a variant classification agnostic approach, biallelic mutations in PRIM1 were identified in five individuals. PRIM1 protein levels were markedly reduced in patient cells, accompanied by replication fork asymmetry, increased interorigin distances, replication stress, and prolonged S-phase duration. Consequently, cell proliferation was markedly impaired, explaining the patients' extreme growth failure. Notably, phenotypic features distinct from those previously reported with DNA polymerase genes were evident, highlighting differing developmental requirements for this core replisome component that warrant future investigation.


Assuntos
DNA Primase/genética , Nanismo/genética , Retardo do Crescimento Fetal/genética , DNA Primase/química , DNA Primase/deficiência , Nanismo/diagnóstico por imagem , Nanismo/patologia , Feminino , Retardo do Crescimento Fetal/diagnóstico por imagem , Retardo do Crescimento Fetal/patologia , Variação Genética , Humanos , Lactente , Masculino , Linhagem , Síndrome
2.
Nature ; 559(7713): 285-289, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29973717

RESUMO

The observation that BRCA1- and BRCA2-deficient cells are sensitive to inhibitors of poly(ADP-ribose) polymerase (PARP) has spurred the development of cancer therapies that use these inhibitors to target deficiencies in homologous recombination1. The cytotoxicity of PARP inhibitors depends on PARP trapping, the formation of non-covalent protein-DNA adducts composed of inhibited PARP1 bound to DNA lesions of unclear origins1-4. To address the nature of such lesions and the cellular consequences of PARP trapping, we undertook three CRISPR (clustered regularly interspersed palindromic repeats) screens to identify genes and pathways that mediate cellular resistance to olaparib, a clinically approved PARP inhibitor1. Here we present a high-confidence set of 73 genes, which when mutated cause increased sensitivity to PARP inhibitors. In addition to an expected enrichment for genes related to homologous recombination, we discovered that mutations in all three genes encoding ribonuclease H2 sensitized cells to PARP inhibition. We establish that the underlying cause of the PARP-inhibitor hypersensitivity of cells deficient in ribonuclease H2 is impaired ribonucleotide excision repair5. Embedded ribonucleotides, which are abundant in the genome of cells deficient in ribonucleotide excision repair, are substrates for cleavage by topoisomerase 1, resulting in PARP-trapping lesions that impede DNA replication and endanger genome integrity. We conclude that genomic ribonucleotides are a hitherto unappreciated source of PARP-trapping DNA lesions, and that the frequent deletion of RNASEH2B in metastatic prostate cancer and chronic lymphocytic leukaemia could provide an opportunity to exploit these findings therapeutically.


Assuntos
Sistemas CRISPR-Cas , Dano ao DNA , Edição de Genes , Neoplasias/genética , Neoplasias/patologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Ribonucleotídeos/genética , Animais , Proteína BRCA1/deficiência , Proteína BRCA1/genética , Linhagem Celular , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/genética , Replicação do DNA , DNA Topoisomerases Tipo I/metabolismo , Feminino , Genes BRCA1 , Genoma/genética , Células HeLa , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/enzimologia , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Ftalazinas/farmacologia , Piperazinas/farmacologia , Poli(ADP-Ribose) Polimerase-1/deficiência , Poli(ADP-Ribose) Polimerase-1/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia , Ribonuclease H/deficiência , Ribonuclease H/genética , Ribonuclease H/metabolismo , Mutações Sintéticas Letais , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Nature ; 548(7668): 461-465, 2017 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-28738408

RESUMO

DNA is strictly compartmentalized within the nucleus to prevent autoimmunity; despite this, cyclic GMP-AMP synthase (cGAS), a cytosolic sensor of double-stranded DNA, is activated in autoinflammatory disorders and by DNA damage. Precisely how cellular DNA gains access to the cytoplasm remains to be determined. Here, we report that cGAS localizes to micronuclei arising from genome instability in a mouse model of monogenic autoinflammation, after exogenous DNA damage and spontaneously in human cancer cells. Such micronuclei occur after mis-segregation of DNA during cell division and consist of chromatin surrounded by its own nuclear membrane. Breakdown of the micronuclear envelope, a process associated with chromothripsis, leads to rapid accumulation of cGAS, providing a mechanism by which self-DNA becomes exposed to the cytosol. cGAS is activated by chromatin, and consistent with a mitotic origin, micronuclei formation and the proinflammatory response following DNA damage are cell-cycle dependent. By combining live-cell laser microdissection with single cell transcriptomics, we establish that interferon-stimulated gene expression is induced in micronucleated cells. We therefore conclude that micronuclei represent an important source of immunostimulatory DNA. As micronuclei formed from lagging chromosomes also activate this pathway, recognition of micronuclei by cGAS may act as a cell-intrinsic immune surveillance mechanism that detects a range of neoplasia-inducing processes.


Assuntos
Instabilidade Genômica/imunologia , Imunidade Inata/genética , Micronúcleos com Defeito Cromossômico , Nucleotidiltransferases/metabolismo , Animais , Ciclo Celular , Linhagem Celular Tumoral , Cromatina/metabolismo , Cromotripsia , Citoplasma/enzimologia , Citoplasma/genética , DNA/metabolismo , Dano ao DNA , Feminino , Instabilidade Genômica/genética , Humanos , Inflamação/enzimologia , Inflamação/genética , Lasers , Masculino , Camundongos , Microdissecção , Mitose , Membrana Nuclear/metabolismo , Nucleotidiltransferases/genética , Análise de Célula Única , Transcriptoma
4.
EMBO J ; 37(15)2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29959219

RESUMO

Long INterspersed Element class 1 (LINE-1) elements are a type of abundant retrotransposons active in mammalian genomes. An average human genome contains ~100 retrotransposition-competent LINE-1s, whose activity is influenced by the combined action of cellular repressors and activators. TREX1, SAMHD1 and ADAR1 are known LINE-1 repressors and when mutated cause the autoinflammatory disorder Aicardi-Goutières syndrome (AGS). Mutations in RNase H2 are the most common cause of AGS, and its activity was proposed to similarly control LINE-1 retrotransposition. It has therefore been suggested that increased LINE-1 activity may be the cause of aberrant innate immune activation in AGS Here, we establish that, contrary to expectations, RNase H2 is required for efficient LINE-1 retrotransposition. As RNase H1 overexpression partially rescues the defect in RNase H2 null cells, we propose a model in which RNase H2 degrades the LINE-1 RNA after reverse transcription, allowing retrotransposition to be completed. This also explains how LINE-1 elements can retrotranspose efficiently without their own RNase H activity. Our findings appear to be at odds with LINE-1-derived nucleic acids driving autoinflammation in AGS.


Assuntos
Doenças Autoimunes do Sistema Nervoso/genética , Elementos Nucleotídeos Longos e Dispersos/genética , Malformações do Sistema Nervoso/genética , Ribonuclease H/genética , Linhagem Celular Tumoral , Técnicas de Inativação de Genes , Células HCT116 , Células HeLa , Humanos , Transcrição Reversa/genética , Ribonuclease H/biossíntese
5.
Mol Cell ; 50(3): 333-43, 2013 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-23623683

RESUMO

The regulation of DNA double-strand break (DSB) repair by phosphorylation-dependent signaling pathways is crucial for the maintenance of genome stability; however, remarkably little is known about the molecular mechanisms by which phosphorylation controls DSB repair. Here, we show that PIN1, a phosphorylation-specific prolyl isomerase, interacts with key DSB repair factors and affects the relative contributions of homologous recombination (HR) and nonhomologous end-joining (NHEJ) to DSB repair. We find that PIN1-deficient cells display reduced NHEJ due to increased DNA end resection, whereas resection and HR are compromised in PIN1-overexpressing cells. Moreover, we identify CtIP as a substrate of PIN1 and show that DSBs become hyperresected in cells expressing a CtIP mutant refractory to PIN1 recognition. Mechanistically, we provide evidence that PIN1 impinges on CtIP stability by promoting its ubiquitylation and subsequent proteasomal degradation. Collectively, these data uncover PIN1-mediated isomerization as a regulatory mechanism coordinating DSB repair.


Assuntos
Reparo do DNA por Junção de Extremidades , DNA/genética , Peptidilprolil Isomerase/genética , Peptidilprolil Isomerase/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular , Quinase 2 Dependente de Ciclina/genética , Quinase 2 Dependente de Ciclina/metabolismo , Quebras de DNA de Cadeia Dupla , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Endodesoxirribonucleases , Instabilidade Genômica , Células HEK293 , Recombinação Homóloga , Humanos , Peptidilprolil Isomerase de Interação com NIMA , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosforilação , Ubiquitinação
6.
Hum Mutat ; 40(8): 1063-1070, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31045292

RESUMO

Microcephalic primordial dwarfism (MPD) is a group of rare single-gene disorders characterized by the extreme reduction in brain and body size from early development onwards. Proteins encoded by MPD-associated genes play important roles in fundamental cellular processes, notably genome replication and repair. Here we report the identification of four MPD individuals with biallelic variants in DNA2, which encodes an adenosine triphosphate (ATP)-dependent helicase/nuclease involved in DNA replication and repair. We demonstrate that the two intronic variants (c.1764-38_1764-37ins(53) and c.74+4A>C) found in these individuals substantially impair DNA2 transcript splicing. Additionally, we identify a missense variant (c.1963A>G), affecting a residue of the ATP-dependent helicase domain that is highly conserved between humans and yeast, with the resulting substitution (p.Thr655Ala) predicted to directly impact ATP/ADP (adenosine diphosphate) binding by DNA2. Our findings support the pathogenicity of these variants as biallelic hypomorphic mutations, establishing DNA2 as an MPD disease gene.


Assuntos
DNA Helicases/genética , Nanismo/genética , Variação Genética , Microcefalia/genética , Adolescente , Alelos , DNA Helicases/química , Feminino , Predisposição Genética para Doença , Humanos , Íntrons , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Mutagênese Insercional , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único
7.
Nature ; 502(7471): 381-4, 2013 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-24005329

RESUMO

Repair of interstrand crosslinks (ICLs) requires the coordinated action of the intra-S-phase checkpoint and the Fanconi anaemia pathway, which promote ICL incision, translesion synthesis and homologous recombination (reviewed in refs 1, 2). Previous studies have implicated the 3'-5' superfamily 2 helicase HELQ in ICL repair in Drosophila melanogaster (MUS301 (ref. 3)) and Caenorhabditis elegans (HELQ-1 (ref. 4)). Although in vitro analysis suggests that HELQ preferentially unwinds synthetic replication fork substrates with 3' single-stranded DNA overhangs and also disrupts protein-DNA interactions while translocating along DNA, little is known regarding its functions in mammalian organisms. Here we report that HELQ helicase-deficient mice exhibit subfertility, germ cell attrition, ICL sensitivity and tumour predisposition, with Helq heterozygous mice exhibiting a similar, albeit less severe, phenotype than the null, indicative of haploinsufficiency. We establish that HELQ interacts directly with the RAD51 paralogue complex BCDX2 and functions in parallel to the Fanconi anaemia pathway to promote efficient homologous recombination at damaged replication forks. Thus, our results reveal a critical role for HELQ in replication-coupled DNA repair, germ cell maintenance and tumour suppression in mammals.


Assuntos
Carcinogênese , DNA Helicases/metabolismo , Reparo do DNA , Células Germinativas/metabolismo , Células Germinativas/patologia , Rad51 Recombinase/metabolismo , Animais , Carcinogênese/genética , Carcinogênese/patologia , Dano ao DNA/genética , DNA Helicases/deficiência , DNA Helicases/genética , Reparo do DNA/genética , Replicação do DNA/genética , Anemia de Fanconi/metabolismo , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/deficiência , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/genética , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/metabolismo , Feminino , Deleção de Genes , Células Germinativas/citologia , Masculino , Camundongos , Complexos Multiproteicos/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Ovário/metabolismo , Ovário/patologia , Reparo de DNA por Recombinação/genética
8.
Cancer Res ; 82(4): 632-647, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-34921014

RESUMO

SRC is a nonreceptor tyrosine kinase with key roles in breast cancer development and progression. Despite this, SRC tyrosine kinase inhibitors have so far failed to live up to their promise in clinical trials, with poor overall response rates. We aimed to identify possible synergistic gene-drug interactions to discover new rational combination therapies for SRC inhibitors. An unbiased genome-wide CRISPR-Cas9 knockout screen in a model of triple-negative breast cancer revealed that loss of integrin-linked kinase (ILK) and its binding partners α-Parvin and PINCH-1 sensitizes cells to bosutinib, a clinically approved SRC/ABL kinase inhibitor. Sensitivity to bosutinib did not correlate with ABL dependency; instead, bosutinib likely induces these effects by acting as a SRC tyrosine kinase inhibitor. Furthermore, in vitro and in vivo models showed that loss of ILK enhanced sensitivity to eCF506, a novel and highly selective inhibitor of SRC with a unique mode of action. Whole-genome RNA sequencing following bosutinib treatment in ILK knockout cells identified broad changes in the expression of genes regulating cell adhesion and cell-extracellular matrix. Increased sensitivity to SRC inhibition in ILK knockout cells was associated with defective adhesion, resulting in reduced cell number as well as increased G1 arrest and apoptosis. These findings support the potential of ILK loss as an exploitable therapeutic vulnerability in breast cancer, enhancing the effectiveness of clinical SRC inhibitors. SIGNIFICANCE: A CRISPR-Cas9 screen reveals that loss of integrin-linked kinase synergizes with SRC inhibition, providing a new opportunity for enhancing the clinical effectiveness of SRC inhibitors in breast cancer.


Assuntos
Neoplasias da Mama/genética , Proliferação de Células/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/genética , Quinases da Família src/antagonistas & inibidores , Compostos de Anilina/farmacologia , Animais , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Estimativa de Kaplan-Meier , Células MCF-7 , Camundongos Knockout , Nitrilas/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Quinolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Quinases da Família src/metabolismo
9.
Mol Genet Genomics ; 282(1): 83-96, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19370360

RESUMO

The mechanisms leading to non-lethality of nonsense mutations in essential genes are poorly understood. Here, we focus on the factors influencing viability of yeast cells bearing premature termination codons (PTCs) in the essential gene SUP45 encoding translation termination factor eRF1. Using a dual reporter system we compared readthrough efficiency of the natural termination codon of SUP45 gene, spontaneous sup45-n (nonsense) mutations, nonsense mutations obtained by site-directed mutagenesis (76Q --> TAA, 242R --> TGA, 317L --> TAG). The nonsense mutations in SUP45 gene were shown to be situated in moderate contexts for readthrough efficiency. We showed that readthrough efficiency of some of the mutations present in the sup45 mutants is not correlated with full-length Sup45 protein amount. This resulted from modification of both sup45 mRNA stability which varies 3-fold among sup45-n mutants and degradation rate of mutant Sup45 proteins. Our results demonstrate that some substitutions in the place of PTCs decrease Sup45 stability. The viability of sup45 nonsense mutants is therefore supported by diverse mechanisms that control the final amount of functional Sup45 in cells.


Assuntos
Códon sem Sentido , Genes Fúngicos , Fatores de Terminação de Peptídeos/genética , Fatores de Terminação de Peptídeos/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Sequência de Bases , DNA Fúngico/genética , Escherichia coli/genética , Escherichia coli/metabolismo , Mutagênese Sítio-Dirigida , Biossíntese de Proteínas , Estabilidade de RNA , RNA Fúngico/genética , RNA Fúngico/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Recombinantes/genética
10.
Nat Genet ; 49(4): 537-549, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28191891

RESUMO

To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication and protect, repair and restart damaged forks. Here we identify downstream neighbor of SON (DONSON) as a novel fork protection factor and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilizes forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATM- and Rad3-related (ATR)-dependent signaling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity and the potentiation of chromosomal instability. Hypomorphic mutations in DONSON substantially reduce DONSON protein levels and impair fork stability in cells from patients, consistent with defective DNA replication underlying the disease phenotype. In summary, we have identified mutations in DONSON as a common cause of microcephalic dwarfism and established DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability.


Assuntos
Replicação do DNA/genética , Proteínas de Ligação a DNA/genética , Nanismo/genética , Instabilidade Genômica/genética , Microcefalia/genética , Mutação/genética , Linhagem Celular , Dano ao DNA/genética , Feminino , Humanos , Masculino
11.
Nat Commun ; 7: 12628, 2016 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-27561354

RESUMO

Human CtIP is a decisive factor in DNA double-strand break repair pathway choice by enabling DNA-end resection, the first step that differentiates homologous recombination (HR) from non-homologous end-joining (NHEJ). To coordinate appropriate and timely execution of DNA-end resection, CtIP function is tightly controlled by multiple protein-protein interactions and post-translational modifications. Here, we identify the Cullin3 E3 ligase substrate adaptor Kelch-like protein 15 (KLHL15) as a new interaction partner of CtIP and show that KLHL15 promotes CtIP protein turnover via the ubiquitin-proteasome pathway. A tripeptide motif (FRY) conserved across vertebrate CtIP proteins is essential for KLHL15-binding; its mutation blocks KLHL15-dependent CtIP ubiquitination and degradation. Consequently, DNA-end resection is strongly attenuated in cells overexpressing KLHL15 but amplified in cells either expressing a CtIP-FRY mutant or lacking KLHL15, thus impacting the balance between HR and NHEJ. Collectively, our findings underline the key importance and high complexity of CtIP modulation for genome integrity.


Assuntos
Proteínas de Transporte/metabolismo , Reparo do DNA por Junção de Extremidades , Recombinação Homóloga/genética , Proteínas dos Microfilamentos/metabolismo , Proteínas Nucleares/metabolismo , Ubiquitinação/genética , Proteínas de Transporte/genética , Linhagem Celular , Proteínas Culina/metabolismo , Quebras de DNA de Cadeia Dupla , Endodesoxirribonucleases , Humanos , Mutação , Proteínas Nucleares/genética , Domínios e Motivos de Interação entre Proteínas/genética , Proteólise
12.
Nat Genet ; 48(1): 36-43, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26595769

RESUMO

DNA lesions encountered by replicative polymerases threaten genome stability and cell cycle progression. Here we report the identification of mutations in TRAIP, encoding an E3 RING ubiquitin ligase, in patients with microcephalic primordial dwarfism. We establish that TRAIP relocalizes to sites of DNA damage, where it is required for optimal phosphorylation of H2AX and RPA2 during S-phase in response to ultraviolet (UV) irradiation, as well as fork progression through UV-induced DNA lesions. TRAIP is necessary for efficient cell cycle progression and mutations in TRAIP therefore limit cellular proliferation, providing a potential mechanism for microcephaly and dwarfism phenotypes. Human genetics thus identifies TRAIP as a component of the DNA damage response to replication-blocking DNA lesions.


Assuntos
Dano ao DNA , Nanismo/genética , Mutação , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Sequência de Aminoácidos , Proliferação de Células/genética , Pré-Escolar , Dano ao DNA/efeitos da radiação , Fácies , Histonas/genética , Histonas/metabolismo , Humanos , Microcefalia/genética , Dados de Sequência Molecular , Fosforilação , Proteína de Replicação A/metabolismo , Fase S/efeitos da radiação , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/genética , Ubiquitina-Proteína Ligases/genética , Raios Ultravioleta
13.
Cell Rep ; 7(4): 1030-8, 2014 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-24794434

RESUMO

The resolution of DNA interstrand crosslinks (ICLs) requires a complex interplay between several processes of DNA metabolism, including the Fanconi anemia (FA) pathway and homologous recombination (HR). FANCD2 monoubiquitination and CtIP-dependent DNA-end resection represent key events in FA and HR activation, respectively, but very little is known about their functional relationship. Here, we show that CtIP physically interacts with both FANCD2 and ubiquitin and that monoubiquitinated FANCD2 tethers CtIP to damaged chromatin, which helps channel DNA double-strand breaks generated during ICL processing into the HR pathway. Consequently, CtIP mutants defective in FANCD2 binding fail to associate with damaged chromatin, which leads to increased levels of nonhomologous end-joining activity and ICL hypersensitivity. Interestingly, we also observe that CtIP depletion aggravates the genomic instability in FANCD2-deficient cells. Thus, our data indicate that FANCD2 primes CtIP-dependent resection during HR after ICL induction but that CtIP helps prevent illegitimate recombination in FA cells.


Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Quebras de DNA de Cadeia Dupla , Reparo do DNA , DNA/metabolismo , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/genética , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Linhagem Celular Tumoral , Instabilidade Cromossômica , DNA/genética , Clivagem do DNA , Endodesoxirribonucleases , Anemia de Fanconi/genética , Anemia de Fanconi/metabolismo , Anemia de Fanconi/patologia , Células HEK293 , Humanos , Transfecção , Ubiquitina/metabolismo
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