Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2017 May 23;114(21):5479-5484. doi: 10.1073/pnas.1705527114. Epub 2017 May 10.

Shelterin components mediate genome reorganization in response to replication stress.

Author information

1
Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892.
2
Howard Hughes Medical Institute, Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605.
3
Genome Analysis Unit, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
4
Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892; grewals@mail.nih.gov.

Abstract

The dynamic nature of genome organization impacts critical nuclear functions including the regulation of gene expression, replication, and DNA damage repair. Despite significant progress, the mechanisms responsible for reorganization of the genome in response to cellular stress, such as aberrant DNA replication, are poorly understood. Here, we show that fission yeast cells carrying a mutation in the DNA-binding protein Sap1 show defects in DNA replication progression and genome stability and display extensive changes in genome organization. Chromosomal regions such as subtelomeres that show defects in replication progression associate with the nuclear envelope in sap1 mutant cells. Moreover, high-resolution, genome-wide chromosome conformation capture (Hi-C) analysis revealed prominent contacts between telomeres and chromosomal arm regions containing replication origins proximal to binding sites for Taz1, a component of the Shelterin telomere protection complex. Strikingly, we find that Shelterin components are required for interactions between Taz1-associated chromosomal arm regions and telomeres. These analyses reveal an unexpected role for Shelterin components in genome reorganization in cells experiencing replication stress, with important implications for understanding the mechanisms governing replication and genome stability.

KEYWORDS:

DNA damage; Shelterin; genome organization; replication; telomeres

PMID:
28490498
PMCID:
PMC5448194
DOI:
10.1073/pnas.1705527114
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center