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Nature

Resumen/Descripción – provisto por la editorial en inglés

Nature is a weekly international journal publishing the finest peer-reviewed research in all fields of science and technology on the basis of its originality, importance, interdisciplinary interest, timeliness, accessibility, elegance and surprising conclusions. Nature also provides rapid, authoritative, insightful and arresting news and interpretation of topical and coming trends affecting science, scientists and the wider public.

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Información

Tipo de recurso:

revistas

ISSN impreso

0028-0836

ISSN electrónico

1476-4687

Editor responsable

Springer Nature

País de edición

Reino Unido

Fecha de publicación

1869-

Cobertura temática

Ciencias naturales

Ingeniería y tecnología

Ciencias médicas y de la salud

Ciencias agrícolas y veterinarias

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doi: 10.1038/s41586-022-04803-0

Cohesin-mediated loop anchors confine the locations of human replication origins

Daniel J. Emerson; Peiyao A. Zhao; Ashley L. Cook; R. Jordan Barnett; Kyle N. Klein; Dalila Saulebekova; Chunmin Ge; Linda Zhou; Zoltan Simandi; Miriam K. Minsk; Katelyn R. Titus; Weitao Wang; Wanfeng Gong; Di Zhang; Liyan Yang; Sergey V. Venev; Johan H. Gibcus; Hongbo Yang; Takayo Sasaki; Masato T. Kanemaki; Feng Yue; Job Dekker; Chun-Long Chen; David M. Gilbert; Jennifer E. Phillips-Cremins

<jats:title>Abstract</jats:title><jats:p>DNA replication occurs through an intricately regulated series of molecular events and is fundamental for genome stability<jats:sup>1,2</jats:sup>. At present, it is unknown how the locations of replication origins are determined in the human genome. Here we dissect the role of topologically associating domains (TADs)<jats:sup>3â€“6</jats:sup>, subTADs<jats:sup>7</jats:sup> and loops<jats:sup>8</jats:sup> in the positioning of replication initiation zones (IZs). We stratify TADsÂ andÂ subTADs by the presence of corner-dots indicative of loops and the orientation of CTCF motifs. We find that high-efficiency, early replicating IZs localize to boundaries between adjacent corner-dot TADs anchored by high-density arrays of divergently and convergently oriented CTCF motifs. By contrast, low-efficiency IZs localize to weaker dotless boundaries. Following ablation of cohesin-mediated loop extrusion during G1, high-efficiency IZs become diffuse and delocalized at boundaries with complex CTCF motif orientations. Moreover, G1 knockdown of the cohesin unloading factor WAPL results in gained long-range loops and narrowed localization of IZs at the same boundaries. Finally, targeted deletion or insertion of specific boundaries causes local replication timing shifts consistent with IZ loss or gain, respectively. Our data support a model in which cohesin-mediated loop extrusion and stalling at a subset of genetically encoded TADÂ andÂ subTAD boundaries is an essential determinant of the locations of replication origins in human S phase.</jats:p>

Palabras clave: Multidisciplinary.

Pp. 812-819