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1.
Cell Rep ; 20(11): 2693-2705, 2017 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-28903048

RESUMEN

Chromatin modification through histone H3 lysine 36 methylation by the SETD2 tumor suppressor plays a key role in maintaining genome stability. Here, we describe a role for Set2-dependent H3K36 methylation in facilitating DNA replication and the transcriptional responses to both replication stress and DNA damage through promoting MluI cell-cycle box (MCB) binding factor (MBF)-complex-dependent transcription in fission yeast. Set2 loss leads to reduced MBF-dependent ribonucleotide reductase (RNR) expression, reduced deoxyribonucleoside triphosphate (dNTP) synthesis, altered replication origin firing, and a checkpoint-dependent S-phase delay. Accordingly, prolonged S phase in the absence of Set2 is suppressed by increasing dNTP synthesis. Furthermore, H3K36 is di- and tri-methylated at these MBF gene promoters, and Set2 loss leads to reduced MBF binding and transcription in response to genotoxic stress. Together, these findings provide new insights into how H3K36 methylation facilitates DNA replication and promotes genotoxic stress responses in fission yeast.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Daño del ADN , Replicación del ADN , N-Metiltransferasa de Histona-Lisina/metabolismo , Proteínas de Schizosaccharomyces pombe/metabolismo , Schizosaccharomyces/enzimología , Schizosaccharomyces/genética , Factores de Transcripción/metabolismo , Transcripción Genética , Puntos de Control del Ciclo Celular/genética , Daño del ADN/genética , Replicación del ADN/genética , ADN de Hongos/metabolismo , Regulación hacia Abajo/genética , Regulación Fúngica de la Expresión Génica , Genes Fúngicos , Mutación/genética , Nucleótidos/metabolismo , Origen de Réplica/genética , Fase S/genética
2.
Nat Commun ; 5: 4091, 2014 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-24909977

RESUMEN

DNA double-strand break (DSB) repair is a highly regulated process performed predominantly by non-homologous end joining (NHEJ) or homologous recombination (HR) pathways. How these pathways are coordinated in the context of chromatin is unclear. Here we uncover a role for histone H3K36 modification in regulating DSB repair pathway choice in fission yeast. We find Set2-dependent H3K36 methylation reduces chromatin accessibility, reduces resection and promotes NHEJ, while antagonistic Gcn5-dependent H3K36 acetylation increases chromatin accessibility, increases resection and promotes HR. Accordingly, loss of Set2 increases H3K36Ac, chromatin accessibility and resection, while Gcn5 loss results in the opposite phenotypes following DSB induction. Further, H3K36 modification is cell cycle regulated with Set2-dependent H3K36 methylation peaking in G1 when NHEJ occurs, while Gcn5-dependent H3K36 acetylation peaks in S/G2 when HR prevails. These findings support an H3K36 chromatin switch in regulating DSB repair pathway choice.


Asunto(s)
Acetiltransferasas/metabolismo , Cromatina/metabolismo , Reparación del ADN por Unión de Extremidades , Reparación del ADN , ADN de Hongos/metabolismo , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/metabolismo , Reparación del ADN por Recombinación , Proteínas de Schizosaccharomyces pombe/metabolismo , Schizosaccharomyces/genética , Acetilación , Metilación , Schizosaccharomyces/metabolismo
3.
Nucleic Acids Res ; 42(9): 5644-56, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24623809

RESUMEN

DNA double-strand breaks (DSBs) can cause chromosomal rearrangements and extensive loss of heterozygosity (LOH), hallmarks of cancer cells. Yet, how such events are normally suppressed is unclear. Here we identify roles for the DNA damage checkpoint pathway in facilitating homologous recombination (HR) repair and suppressing extensive LOH and chromosomal rearrangements in response to a DSB. Accordingly, deletion of Rad3(ATR), Rad26ATRIP, Crb2(53BP1) or Cdc25 overexpression leads to reduced HR and increased break-induced chromosome loss and rearrangements. We find the DNA damage checkpoint pathway facilitates HR, in part, by promoting break-induced Cdt2-dependent nucleotide synthesis. We also identify additional roles for Rad17, the 9-1-1 complex and Chk1 activation in facilitating break-induced extensive resection and chromosome loss, thereby suppressing extensive LOH. Loss of Rad17 or the 9-1-1 complex results in a striking increase in break-induced isochromosome formation and very low levels of chromosome loss, suggesting the 9-1-1 complex acts as a nuclease processivity factor to facilitate extensive resection. Further, our data suggest redundant roles for Rad3ATR and Exo1 in facilitating extensive resection. We propose that the DNA damage checkpoint pathway coordinates resection and nucleotide synthesis, thereby promoting efficient HR repair and genome stability.


Asunto(s)
Roturas del ADN de Doble Cadena , División del ADN , Inestabilidad Genómica , Reparación del ADN por Recombinación , Schizosaccharomyces/genética , Puntos de Control del Ciclo Celular , Quinasa de Punto de Control 2/metabolismo , Cromosomas Fúngicos/genética , Hibridación Genómica Comparativa , Exodesoxirribonucleasas/metabolismo , Genoma Fúngico , Pérdida de Heterocigocidad , Nucleótidos/biosíntesis , Schizosaccharomyces/metabolismo , Proteínas de Schizosaccharomyces pombe/metabolismo
4.
Nucleic Acids Res ; 39(14): 5978-90, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21493688

RESUMEN

Cdt1 plays a critical role in DNA replication regulation by controlling licensing. In Metazoa, Cdt1 is regulated by CRL4(Cdt2)-mediated ubiquitylation, which is triggered by DNA binding of proliferating cell nuclear antigen (PCNA). We show here that fission yeast Cdt1 interacts with PCNA in vivo and that DNA loading of PCNA is needed for Cdt1 proteolysis after DNA damage and in S phase. Activation of this pathway by ultraviolet (UV)-induced DNA damage requires upstream involvement of nucleotide excision repair or UVDE repair enzymes. Unexpectedly, two non-canonical PCNA-interacting peptide (PIP) motifs, which both have basic residues downstream, function redundantly in Cdt1 proteolysis. Finally, we show that poly-ubiquitylation of PCNA, which occurs after DNA damage, reduces Cdt1 proteolysis. This provides a mechanism for fine-tuning the activity of the CRL4(Cdt2) pathway towards Cdt1, allowing Cdt1 proteolysis to be more efficient in S phase than after DNA damage.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Daño del ADN , Proteínas de Unión al ADN/metabolismo , Antígeno Nuclear de Célula en Proliferación/metabolismo , Proteínas de Schizosaccharomyces pombe/metabolismo , Ubiquitinación , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Proteínas de Ciclo Celular/química , Cromatina/metabolismo , ADN de Hongos/metabolismo , Proteínas de Unión al ADN/química , Datos de Secuencia Molecular , Fase S/genética , Schizosaccharomyces/genética , Schizosaccharomyces/metabolismo , Schizosaccharomyces/efectos de la radiación , Proteínas de Schizosaccharomyces pombe/química , Rayos Ultravioleta
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