Loss of ATRX, Genome Instability, and an Altered DNA Damage Response Are Hallmarks of the Alternative Lengthening of Telomeres Pathway

Lovejoy, Courtney A.; Li, Wendi; Reisenweber, Steven; Thongthip, Supawat; Bruno, Joanne; Lange, Titia de; De, Saurav; Petrini, John H.J.; Sung, Patricia; Jasin, Maria; Rosenbluh, Joseph; Zwang, Yaara; Weir, Barbara A.; Hatton, Charlie; Ivanova, Elena; MacConaill, Laura E.; Hanna, Megan; Hahn, William C.; Lue, Neal F.; Reddel, Roger R.; Jiao, Yuchen; Kinzler, Kenneth W.; Vogelstein, Bert; Papadopoulos, Nickolas; Meeker, Alan K.

doi:10.1371/journal.pgen.1002772

Cited by 508 publications

(621 citation statements)

References 57 publications

(60 reference statements)

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“…When we looked for colocalization of ATRX with telomeres, we did not find any significant differences between in ATRX colocalization with telomeres in the mESC E14 and 408 cell lines ( Supporting Information Figs. S3A and 3B), whereas the two mESC lines showed high frequencies of ATRX in contrast to published work where ATRX was mutated in the ALT‐positive human cells, including U2OS (Lovejoy et al, 2012). Finally, when we looked at colocalization of BRCA1 with ATRX and BLM (Figs.…”

Section: Resultscontrasting

confidence: 71%

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Analysis of alternative lengthening of telomere markers in BRCA1 defective cells

Kargaran

Yasaei

Anjomani-Virmouni

et al. 2016

Genes Chromosomes & Cancer

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Telomeres are specialized structures responsible for the chromosome end protection. Previous studies have revealed that defective BRCA1 may lead to elevated telomere fusions and accelerated telomere shortening. In addition, BRCA1 associates with promyelocytic leukemia (PML) bodies in alternative lengthening of telomeres (ALTs) positive cells. We report here elevated recombination rates at telomeres in cells from human BRCA1 mutation carriers and in mouse embryonic stem cells lacking both copies of functional Brca1. An increased recombination rate at telomeres is one of the signs of ALT. To investigate this possibility further we employed the C‐circle assay that identifies ALT unequivocally. Our results revealed elevated levels of ALT activity in Brca1 defective mouse cells. Similar results were obtained when the same cells were assayed for the presence of another ALT marker, namely the frequency of PML bodies. These results suggest that BRCA1 may act as a repressor of ALT. © 2016 The Authors Genes, Chromosomes & Cancer Published by Wiley Periodicals, Inc.

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Section: Resultscontrasting

confidence: 71%

“…A recent study indicated that mutations in ATRX (alpha thalassemia/mental retardation syndrome X‐linked) are associated with ALT activation in 90% of human ALT‐positive cells (Lovejoy et al, 2012). As expected, the U2OS cell line did not show staining with the ATRX antibody in contrast to nonALT cell lines ( Supporting Information Fig.…”

Section: Resultsmentioning

confidence: 99%

Analysis of alternative lengthening of telomere markers in BRCA1 defective cells

Kargaran

Yasaei

Anjomani-Virmouni

et al. 2016

Genes Chromosomes & Cancer

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“…Though its functional significance remains to be tested, the reduction in chromatin-bound CENP-A raises a possibility that centromere instability in cancer cells may be in part due to compromised functionality of CENP-A and CCAN proteins. In U2OS cells, ATRX is deleted and telomere is maintained via the alternative lengthening of telomeres (ALT) pathway (30). It has been recently shown that C-SCE is enhanced in mouse embryos lacking ATRX, and suggested that this hyperrecombination may result in chromosome breakage at the centromere and fusion (25).…”

Section: Cenp-a-dependent Mechanism To Maintain Centromere Integritymentioning

confidence: 99%

Integrity of the human centromere DNA repeats is protected by CENP-A, CENP-C, and CENP-T

Giunta

Funabiki

2017

Proc. Natl. Acad. Sci. U.S.A.

105

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Centromeres are highly specialized chromatin domains that enable chromosome segregation and orchestrate faithful cell division. Human centromeres are composed of tandem arrays of α-satellite DNA, which spans up to several megabases. Little is known about the mechanisms that maintain integrity of the long arrays of α-satellite DNA repeats. Here, we monitored centromeric repeat stability in human cells using chromosome-orientation fluorescent in situ hybridization (CO-FISH). This assay detected aberrant centromeric CO-FISH patterns consistent with sister chromatid exchange at the frequency of 5% in primary tissue culture cells, whereas higher levels were seen in several cancer cell lines and during replicative senescence. To understand the mechanism(s) that maintains centromere integrity, we examined the contribution of the centromere-specific histone variant CENP-A and members of the constitutive centromere-associated network (CCAN), CENP-C, CENP-T, and CENP-W. Depletion of CENP-A and CCAN proteins led to an increase in centromere aberrations, whereas enhancing chromosome missegregation by alternative methods did not, suggesting that CENP-A and CCAN proteins help maintain centromere integrity independently of their role in chromosome segregation. Furthermore, superresolution imaging of centromeric CO-FISH using structured illumination microscopy implied that CENP-A protects α-satellite repeats from extensive rearrangements. Our study points toward the presence of a centromere-specific mechanism that actively maintains α-satellite repeat integrity during human cell proliferation.centromere | genome integrity | α-satellite repeats | cancer | CO-FISH

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“…Subsequent studies have reported frequent ATRX loss (but not DAXX loss) in astrocytoma, leiomyosarcoma, dedifferentiated liposarcoma and other tumor types, and the loss of ATRX has been highly correlated with the alternative lengthening of telomeres phenotype. 6,12,13,[17][18][19][20][21] However, knockdown of ATRX or DAXX has not led to alternative lengthening of telomeres, and patients with germline ATRX mutations do not appear to be cancer prone. 18,22 In addition, although loss of either ATRX or DAXX is perfectly associated with alternative lengthening of telomeres in pancreatic neuroendocrine tumors, the situation is more complex in sarcomas.…”

mentioning

confidence: 99%

“…6,12,13,[17][18][19][20][21] However, knockdown of ATRX or DAXX has not led to alternative lengthening of telomeres, and patients with germline ATRX mutations do not appear to be cancer prone. 18,22 In addition, although loss of either ATRX or DAXX is perfectly associated with alternative lengthening of telomeres in pancreatic neuroendocrine tumors, the situation is more complex in sarcomas. In our previous studies, only approximately half of alternative lengthening of telomerespositive leiomyosarcomas and pleomorphic liposarcomas were ATRX deficient, 6,12 but alternative lengthening of telomeres was highly correlated with loss of ATRX in angiosarcomas and dedifferentiated liposarcomas.…”

mentioning

confidence: 99%

Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas

et al. 2015

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According to cytogenetic aberrations, sarcomas can be categorized as complex or simple karyotype tumors. Alternative lengthening of telomeres is a telomere-maintenance mechanism common in sarcomas. Recently, this mechanism was found to be associated with loss of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein. We previously reported that alternative lengthening of telomeres and loss of ATRX expression were common in leiomyosarcoma, angiosarcoma, pleomorphic liposarcoma, and dedifferentiated liposarcoma. In the present study, we screened an additional 245 sarcomas of other types to determine the prevalence of alternative lengthening of telomeres, loss of ATRX/DAXX expression, and their relationship. Undifferentiated pleomorphic sarcomas were frequently alternative lengthening of telomeres positive (65%) and loss of ATRX was seen in approximately half of the alternative lengthening of telomeres-positive tumors. Nineteen of 25 myxofibrosarcomas were alternative lengthening of telomerespositive, but only one was ATRX deficient. Three of 15 radiation-associated sarcomas were alternative lengthening of telomeres positive, but none of them was ATRX deficient. Alternative lengthening of telomeres and/or loss of ATRX were uncommon in malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, and embryonal rhabdomyosarcomas. By contrast, none of the 71 gene fusion-associated sarcomas was ATRX deficient or alternative lengthening of telomeres positive. All tumors exhibited preserved DAXX expression. Combining our previous studies and this study, a total of 384 sarcomas with complex karyotypes were examined, 83 of which were ATRX deficient (22%). By telomere-specific fluorescence in situ hybridization, 45% (138/308) were alternative lengthening of telomeres positive, 55% (76/138) of which were ATRX deficient. Loss of ATRX was highly associated with alternative lengthening of telomeres (Po 0.001). We conclude that alternative lengthening of telomeres is a frequent telomere-maintenance mechanism in cytogenetically complex sarcomas. Loss of ATRX is highly associated with this feature.

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Loss of ATRX, Genome Instability, and an Altered DNA Damage Response Are Hallmarks of the Alternative Lengthening of Telomeres Pathway

Cited by 508 publications

References 57 publications

Analysis of alternative lengthening of telomere markers in BRCA1 defective cells

Analysis of alternative lengthening of telomere markers in BRCA1 defective cells

Integrity of the human centromere DNA repeats is protected by CENP-A, CENP-C, and CENP-T

Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas

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