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1.
Nature ; 600(7887): 158-163, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34819667

RESUMO

Endogenous DNA damage can perturb transcription, triggering a multifaceted cellular response that repairs the damage, degrades RNA polymerase II and shuts down global transcription1-4. This response is absent in the human disease Cockayne syndrome, which is caused by loss of the Cockayne syndrome A (CSA) or CSB proteins5-7. However, the source of endogenous DNA damage and how this leads to the prominent degenerative features of this disease remain unknown. Here we find that endogenous formaldehyde impedes transcription, with marked physiological consequences. Mice deficient in formaldehyde clearance (Adh5-/-) and CSB (Csbm/m; Csb is also known as Ercc6) develop cachexia and neurodegeneration, and succumb to kidney failure, features that resemble human Cockayne syndrome. Using single-cell RNA sequencing, we find that formaldehyde-driven transcriptional stress stimulates the expression of the anorexiogenic peptide GDF15 by a subset of kidney proximal tubule cells. Blocking this response with an anti-GDF15 antibody alleviates cachexia in Adh5-/-Csbm/m mice. Therefore, CSB provides protection to the kidney and brain against DNA damage caused by endogenous formaldehyde, while also suppressing an anorexic endocrine signal. The activation of this signal might contribute to the cachexia observed in Cockayne syndrome as well as chemotherapy-induced anorectic weight loss. A plausible evolutionary purpose for such a response is to ensure aversion to genotoxins in food.


Assuntos
Síndrome de Cockayne , Dano ao DNA , Formaldeído/efeitos adversos , Estresse Fisiológico/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacos , Álcool Desidrogenase/deficiência , Álcool Desidrogenase/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Caquexia/complicações , Síndrome de Cockayne/induzido quimicamente , Síndrome de Cockayne/complicações , Síndrome de Cockayne/genética , Síndrome de Cockayne/patologia , Enzimas Reparadoras do DNA/deficiência , Modelos Animais de Doenças , Feminino , Formaldeído/metabolismo , Fator 15 de Diferenciação de Crescimento/antagonistas & inibidores , Fator 15 de Diferenciação de Crescimento/biossíntese , Fator 15 de Diferenciação de Crescimento/genética , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Masculino , Camundongos , Proteínas de Ligação a Poli-ADP-Ribose/deficiência , Insuficiência Renal/complicações , Transcrição Gênica/genética
2.
Nature ; 553(7687): 171-177, 2018 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-29323295

RESUMO

Haematopoietic stem cells renew blood. Accumulation of DNA damage in these cells promotes their decline, while misrepair of this damage initiates malignancies. Here we describe the features and mutational landscape of DNA damage caused by acetaldehyde, an endogenous and alcohol-derived metabolite. This damage results in DNA double-stranded breaks that, despite stimulating recombination repair, also cause chromosome rearrangements. We combined transplantation of single haematopoietic stem cells with whole-genome sequencing to show that this damage occurs in stem cells, leading to deletions and rearrangements that are indicative of microhomology-mediated end-joining repair. Moreover, deletion of p53 completely rescues the survival of aldehyde-stressed and mutated haematopoietic stem cells, but does not change the pattern or the intensity of genome instability within individual stem cells. These findings characterize the mutation of the stem-cell genome by an alcohol-derived and endogenous source of DNA damage. Furthermore, we identify how the choice of DNA-repair pathway and a stringent p53 response limit the transmission of aldehyde-induced mutations in stem cells.


Assuntos
Acetaldeído/metabolismo , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Etanol/metabolismo , Etanol/farmacologia , Instabilidade Genômica/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/patologia , Mutação , Álcool Desidrogenase/deficiência , Álcool Desidrogenase/genética , Álcool Desidrogenase/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Reparo do DNA por Junção de Extremidades , Etanol/administração & dosagem , Anemia de Fanconi/genética , Anemia de Fanconi/metabolismo , Anemia de Fanconi/patologia , 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 , Genes p53/genética , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/metabolismo , Autoantígeno Ku/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Reparo de DNA por Recombinação/efeitos dos fármacos , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Sequenciamento Completo do Genoma
3.
Nature ; 548(7669): 549-554, 2017 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-28813411

RESUMO

The folate-driven one-carbon (1C) cycle is a fundamental metabolic hub in cells that enables the synthesis of nucleotides and amino acids and epigenetic modifications. This cycle might also release formaldehyde, a potent protein and DNA crosslinking agent that organisms produce in substantial quantities. Here we show that supplementation with tetrahydrofolate, the essential cofactor of this cycle, and other oxidation-prone folate derivatives kills human, mouse and chicken cells that cannot detoxify formaldehyde or that lack DNA crosslink repair. Notably, formaldehyde is generated from oxidative decomposition of the folate backbone. Furthermore, we find that formaldehyde detoxification in human cells generates formate, and thereby promotes nucleotide synthesis. This supply of 1C units is sufficient to sustain the growth of cells that are unable to use serine, which is the predominant source of 1C units. These findings identify an unexpected source of formaldehyde and, more generally, indicate that the detoxification of this ubiquitous endogenous genotoxin creates a benign 1C unit that can sustain essential metabolism.


Assuntos
Carbono/metabolismo , Ácido Fólico/química , Ácido Fólico/metabolismo , Formaldeído/química , Formaldeído/metabolismo , Redes e Vias Metabólicas , Mutagênicos/química , Mutagênicos/metabolismo , Álcool Desidrogenase/metabolismo , Animais , Carbono/deficiência , Linhagem Celular , Galinhas , Coenzimas/metabolismo , Reagentes de Ligações Cruzadas/metabolismo , Dano ao DNA , Reparo do DNA , Humanos , Inativação Metabólica , Camundongos , Nucleotídeos/biossíntese , Oxirredução , Serina/química , Serina/metabolismo , Tetra-Hidrofolatos/metabolismo
5.
PLoS Genet ; 16(4): e1008555, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32271760

RESUMO

Loss of the XPF-ERCC1 endonuclease causes a dramatic phenotype that results in progeroid features associated with liver, kidney and bone marrow dysfunction. As this nuclease is involved in multiple DNA repair transactions, it is plausible that this severe phenotype results from the simultaneous inactivation of both branches of nucleotide excision repair (GG- and TC-NER) and Fanconi anaemia (FA) inter-strand crosslink (ICL) repair. Here we use genetics in human cells and mice to investigate the interaction between the canonical NER and ICL repair pathways and, subsequently, how their joint inactivation phenotypically overlaps with XPF-ERCC1 deficiency. We find that cells lacking TC-NER are sensitive to crosslinking agents and that there is a genetic interaction between NER and FA in the repair of certain endogenous crosslinking agents. However, joint inactivation of GG-NER, TC-NER and FA crosslink repair cannot account for the hypersensitivity of XPF-deficient cells to classical crosslinking agents nor is it sufficient to explain the extreme phenotype of Ercc1-/- mice. These analyses indicate that XPF-ERCC1 has important functions outside of its central role in NER and FA crosslink repair which are required to prevent endogenous DNA damage. Failure to resolve such damage leads to loss of tissue homeostasis in mice and humans.


Assuntos
Reparo do DNA , Proteínas de Ligação a DNA/metabolismo , Endonucleases/metabolismo , Homeostase , Animais , Sangue , Reagentes de Ligações Cruzadas/farmacologia , Dano ao DNA , Reparo do DNA/genética , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Endonucleases/deficiência , Endonucleases/genética , Feminino , Formaldeído/farmacologia , Humanos , Rim/enzimologia , Fígado/enzimologia , Masculino , Camundongos
6.
Nature ; 463(7279): 360-3, 2010 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-20054297

RESUMO

Clear cell renal cell carcinoma (ccRCC) is the most common form of adult kidney cancer, characterized by the presence of inactivating mutations in the VHL gene in most cases, and by infrequent somatic mutations in known cancer genes. To determine further the genetics of ccRCC, we have sequenced 101 cases through 3,544 protein-coding genes. Here we report the identification of inactivating mutations in two genes encoding enzymes involved in histone modification-SETD2, a histone H3 lysine 36 methyltransferase, and JARID1C (also known as KDM5C), a histone H3 lysine 4 demethylase-as well as mutations in the histone H3 lysine 27 demethylase, UTX (KMD6A), that we recently reported. The results highlight the role of mutations in components of the chromatin modification machinery in human cancer. Furthermore, NF2 mutations were found in non-VHL mutated ccRCC, and several other probable cancer genes were identified. These results indicate that substantial genetic heterogeneity exists in a cancer type dominated by mutations in a single gene, and that systematic screens will be key to fully determining the somatic genetic architecture of cancer.


Assuntos
Carcinoma de Células Renais/genética , Genes da Neurofibromatose 2 , Histona-Lisina N-Metiltransferase/genética , Histonas/metabolismo , Neoplasias Renais/genética , Proteínas Nucleares/genética , Oxirredutases N-Desmetilantes/genética , Carcinoma de Células Renais/patologia , Hipóxia Celular/genética , Cromatina/metabolismo , Regulação Neoplásica da Expressão Gênica , Histona Desmetilases , Humanos , Neoplasias Renais/patologia , Mutação/genética , Análise de Sequência de DNA
7.
Nat Genet ; 41(5): 521-3, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19330029

RESUMO

Somatically acquired epigenetic changes are present in many cancers. Epigenetic regulation is maintained via post-translational modifications of core histones. Here, we describe inactivating somatic mutations in the histone lysine demethylase gene UTX, pointing to histone H3 lysine methylation deregulation in multiple tumor types. UTX reintroduction into cancer cells with inactivating UTX mutations resulted in slowing of proliferation and marked transcriptional changes. These data identify UTX as a new human cancer gene.


Assuntos
Mutação , Neoplasias/enzimologia , Neoplasias/genética , Oxirredutases N-Desmetilantes/genética , Epigênese Genética , Humanos , Histona Desmetilases com o Domínio Jumonji
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