Chromosoma

, Volume 121, Issue 5, pp 465–474

A TRF1-controlled common fragile site containing interstitial telomeric sequences

Research Article

DOI: 10.1007/s00412-012-0377-6

Cite this article as:
Bosco, N. & de Lange, T. Chromosoma (2012) 121: 465. doi:10.1007/s00412-012-0377-6

Abstract

Mouse telomeres have been suggested to resemble common fragile sites (CFS), showing disrupted TTAGGG fluorescent in situ hybridization signals after aphidicolin treatment. This “fragile” telomere phenotype is induced by deletion of TRF1, a shelterin protein that binds telomeric DNA and promotes efficient replication of the telomeric ds[TTAGGG]n tracts. Here we show that the chromosome-internal TTAGGG repeats present at human chromosome 2q14 form an aphidicolin-induced CFS. TRF1 binds to and stabilizes CFS 2q14 but does not affect other CFS, establishing 2q14 as the first CFS controlled by a sequence-specific DNA binding protein. The data show that telomeric DNA is inherently fragile regardless of its genomic position and imply that CFS can be caused by a specific DNA sequence.

Supplementary material

412_2012_377_MOESM1_ESM.docx (65 kb)
Supplementary Table 1Frequency of CFS 2q14 (Fig. 3b), N-FRA, FRA3B, FRA7H and FRA16D expression (Fig. 3i) after shTRF1 treatment. (DOCX 64 kb)
412_2012_377_MOESM2_ESM.docx (55 kb)
Supplementary Table 2Frequency of CFS 2q14 (Fig. 3d), N-FRA, FRA3B, FRA7H and FRA16D expression (Fig. 3j) after shTRF2 treatment. (DOCX 54 kb)
412_2012_377_MOESM3_ESM.docx (32 kb)
Supplementary Table 3Frequency of CFS 2q14 after treatment with shBLM and shTRF1 (Fig. 4e). (DOCX 32 kb)
412_2012_377_MOESM4_ESM.docx (65 kb)
Supplementary Table 4Frequency of NFRA, FRA3B, FRA7H and FRA16D after treatment with shBLM and shTRF1 (Fig. 4f). (DOCX 64 kb)
412_2012_377_MOESM5_ESM.docx (42 kb)
Supplementary Table 5Frequency of CFS 2q14 (Fig. 5d), FRA3B and FRA16D (Fig. 5c) after treatment with shATR. (DOCX 42 kb)
412_2012_377_MOESM6_ESM.docx (48 kb)
Supplementary Table 6Frequency of CFS 2q14 (Fig. 5g), FRA3B and FRA16D expression (Fig. 5f) in HCT116 ATRflox/- cells after deletion of ATR. (DOCX 47 kb)
412_2012_377_Fig6_ESM.jpg (952 kb)
Fig. S1

The human chromosome 2q14 region. a. DNA sequence from 2q14.1 containing the telomere fusion of two ancestral ape chromosomes. Highlighted are the recognition sites for the TRF1 Myb/SANT DNA binding domain (TAGGGTT or AACCCTA in the other strand). b. Sequence from the genomic locus encoding the Rap1 (TERF1, TRF2 interacting factor 1) gene on chromosome 16, which does not contain TRF1 binding sites. The underlined sequences in both panels indicate the positions of the qPCR primers given in the methods section. (JPEG 951 kb)

412_2012_377_MOESM7_ESM.tif (989 kb)
High resolution image (TIFF 989 kb)
412_2012_377_Fig7_ESM.jpg (160 kb)
Fig. S1

The human chromosome 2q14 region. a. DNA sequence from 2q14.1 containing the telomere fusion of two ancestral ape chromosomes. Highlighted are the recognition sites for the TRF1 Myb/SANT DNA binding domain (TAGGGTT or AACCCTA in the other strand). b. Sequence from the genomic locus encoding the Rap1 (TERF1, TRF2 interacting factor 1) gene on chromosome 16, which does not contain TRF1 binding sites. The underlined sequences in both panels indicate the positions of the qPCR primers given in the methods section. (JPEG 951 kb)

412_2012_377_MOESM8_ESM.tif (3.5 mb)
High resolution image (TIFF 3610 kb)
412_2012_377_Fig8_ESM.jpg (142 kb)
Fig. S1

The human chromosome 2q14 region. a. DNA sequence from 2q14.1 containing the telomere fusion of two ancestral ape chromosomes. Highlighted are the recognition sites for the TRF1 Myb/SANT DNA binding domain (TAGGGTT or AACCCTA in the other strand). b. Sequence from the genomic locus encoding the Rap1 (TERF1, TRF2 interacting factor 1) gene on chromosome 16, which does not contain TRF1 binding sites. The underlined sequences in both panels indicate the positions of the qPCR primers given in the methods section. (JPEG 951 kb)

412_2012_377_MOESM9_ESM.tif (358 kb)
High resolution image (TIFF 358 kb)

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  1. 1.Laboratory for Cell Biology and GeneticsThe Rockefeller UniversityNew YorkUSA