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Mol Cell. 2018 May 3;70(3):449-461.e5. doi: 10.1016/j.molcel.2018.03.036.

Genome-wide Control of Heterochromatin Replication by the Telomere Capping Protein TRF2.

Author information

1
Shanghai Ruijin Hospital, Shanghai Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Université Côte d'Azur, CNRS, Inserm, "Laboratoire International Associé" (LIA) Hematology and Cancer, State Key Laboratory of Medical Genomics, "Pôle Sino-Français de Recherche en Sciences du Vivant et Génomique," Shanghai, P.R. China; Université Côte d'Azur, CNRS, Inserm, IRCAN, Faculty of Medicine Nice, France.
2
Université Côte d'Azur, CNRS, Inserm, IRCAN, Faculty of Medicine Nice, France.
3
Institut Gustave Roussy, Sorbonne Universités, UPMC University, Paris, France; CNRS, UMR 8200, Villejuif, France.
4
Université Côte d'Azur, CNRS, IPMC, France.
5
Institut Curie, PSL University, Sorbonne Universités, UPMC University, CNRS, UMR3664, Paris, France.
6
Institut Curie, PSL University, Sorbonne Universités, UPMC, CNRS, Inserm, UMR9187/U1196, Orsay, France.
7
Institut Curie, PSL Research University, Sorbonne Universités, CNRS UMR3244 Telomere and Cancer Lab, Paris, France.
8
Institut Gustave Roussy, Sorbonne Universités, UPMC University, Paris, France.
9
Shanghai Ruijin Hospital, Shanghai Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Université Côte d'Azur, CNRS, Inserm, "Laboratoire International Associé" (LIA) Hematology and Cancer, State Key Laboratory of Medical Genomics, "Pôle Sino-Français de Recherche en Sciences du Vivant et Génomique," Shanghai, P.R. China; Université Côte d'Azur, CNRS, Inserm, IRCAN, Faculty of Medicine Nice, France; Department of Genetics, CHU, Nice, France. Electronic address: eric.gilson@unice.fr.
10
Shanghai Ruijin Hospital, Shanghai Ruijin Hospital North, Shanghai Jiao Tong University School of Medicine, Université Côte d'Azur, CNRS, Inserm, "Laboratoire International Associé" (LIA) Hematology and Cancer, State Key Laboratory of Medical Genomics, "Pôle Sino-Français de Recherche en Sciences du Vivant et Génomique," Shanghai, P.R. China. Electronic address: yj11254@rjh.com.cn.

Abstract

Hard-to-replicate regions of chromosomes (e.g., pericentromeres, centromeres, and telomeres) impede replication fork progression, eventually leading, in the event of replication stress, to chromosome fragility, aging, and cancer. Our knowledge of the mechanisms controlling the stability of these regions is essentially limited to telomeres, where fragility is counteracted by the shelterin proteins. Here we show that the shelterin subunit TRF2 ensures progression of the replication fork through pericentromeric heterochromatin, but not centromeric chromatin. In a process involving its N-terminal basic domain, TRF2 binds to pericentromeric Satellite III sequences during S phase, allowing the recruitment of the G-quadruplex-resolving helicase RTEL1 to facilitate fork progression. We also show that TRF2 is required for the stability of other heterochromatic regions localized throughout the genome, paving the way for future research on heterochromatic replication and its relationship with aging and cancer.

KEYWORDS:

DNA combing; DNA topology; G-quadruplex; RTEL1; TRF2; centromeres; heterochromatin; pericentromere; replication; telomere

PMID:
29727617
DOI:
10.1016/j.molcel.2018.03.036
[Indexed for MEDLINE]

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