A TIN2 dyskeratosis congenita mutation causes telomerase-independent telomere shortening in mice.

Abstract:

:The progressive bone marrow failure syndrome dyskeratosis congenita (DC) is often caused by mutations in telomerase or the factors involved in telomerase biogenesis and trafficking. However, a subset of DC patients is heterozygous for mutations in the shelterin component TIN2. To determine how the TIN2-DC mutations affect telomere function, we generated mice with the equivalent of the TIN2 K280E DC allele (TIN2(DC)) by gene targeting. Whereas homozygous TIN2(DC/DC) mice were not viable, first-generation TIN2(+/DC) mice were healthy and fertile. In the second and third generations, the TIN2(+/DC) mice developed mild pancytopenia, consistent with hematopoietic dysfunction in DC, as well as diminished fecundity. Bone marrow telomeres of TIN2(+/DC) mice shortened over the generations, and immortalized TIN2(+/DC) mouse embryonic fibroblasts (MEFs) showed telomere shortening with proliferation. Unexpectedly, telomere shortening was accelerated in TIN2(+/DC) mTR(-/-) mice and MEFs compared with TIN2(+/+) mTR(-/-) controls, establishing that the TIN2(DC) telomere maintenance defect was not solely due to diminished telomerase action. The TIN2(DC) allele induced mild ATR kinase signaling at telomeres and a fragile telomere phenotype, suggestive of telomere replication problems. These data suggest that this TIN2-DC mutation could induce telomeric dysfunction phenotypes in telomerase-negative somatic cells and tissues that further exacerbate the telomere maintenance problems in telomerase-positive stem cell compartments.

journal_name

Genes Dev

journal_title

Genes & development

authors

Frescas D,de Lange T

doi

10.1101/gad.233395.113

subject

Has Abstract

pub_date

2014-01-15 00:00:00

pages

153-66

issue

2

eissn

0890-9369

issn

1549-5477

pii

28/2/153

journal_volume

28

pub_type

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