DNA damage response protein TOPBP1 regulates X chromosome silencing in the mammalian germ line.
Proc Natl Acad Sci U S A
; 114(47): 12536-12541, 2017 11 21.
Article
en En
| MEDLINE
| ID: mdl-29114052
ABSTRACT
Meiotic synapsis and recombination between homologs permits the formation of cross-overs that are essential for generating chromosomally balanced sperm and eggs. In mammals, surveillance mechanisms eliminate meiotic cells with defective synapsis, thereby minimizing transmission of aneuploidy. One such surveillance mechanism is meiotic silencing, the inactivation of genes located on asynapsed chromosomes, via ATR-dependent serine-139 phosphorylation of histone H2AFX (γH2AFX). Stimulation of ATR activity requires direct interaction with an ATR activation domain (AAD)-containing partner. However, which partner facilitates the meiotic silencing properties of ATR is unknown. Focusing on the best-characterized example of meiotic silencing, meiotic sex chromosome inactivation, we reveal this AAD-containing partner to be the DNA damage and checkpoint protein TOPBP1. Conditional TOPBP1 deletion during pachynema causes germ cell elimination associated with defective X chromosome gene silencing and sex chromosome condensation. TOPBP1 is essential for localization to the X chromosome of silencing "sensors," including BRCA1, and effectors, including ATR, γH2AFX, and canonical repressive histone marks. We present evidence that persistent DNA double-strand breaks act as silencing initiation sites. Our study identifies TOPBP1 as a critical factor in meiotic sex chromosome silencing.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Cromosomas Sexuales
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Espermatogénesis
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Proteínas Portadoras
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Inactivación del Cromosoma X
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Roturas del ADN de Doble Cadena
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Año:
2017
Tipo del documento:
Article
País de afiliación:
Reino Unido