Tpp1/Acd maintains genomic stability through a complex role in telomere protection

Else, Tobias; Theisen, Brian; Wu, Yue; Hutz, Janna; Keegan, Catherine E.; Hammer, Gary D.; Ferguson, David O.

doi:10.1007/s10577-007-1175-5

Cited by 32 publications

(35 citation statements)

References 47 publications

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“…Both outcomes cause premature termination of translation and a truncated protein lacking all functional domains. Homozygosity for acd decreases the expression of WT transcripts to approximately 2% of normal levels, consistent with a profoundly hypomorphic phenotype (35). Analysis of the fetal livers from E13.5 acd-mutant mice revealed a mild decrease in fetal liver cellularity compared with that in the control littermates ( Figure 1B).…”

Section: Acd Deficiency Results In Cell Cycle Arrest and Impaired Funmentioning

confidence: 61%

“…This allele was originally described to cause adrenocortical dysplasia and was thus named acd (30). It is characterized by a G to A transition within the third intron ( Figure 1A), resulting in aberrant splicing and either a 7-bp insertion after exon 3 or inclusion of the third intron in the mRNA (30,35). Both outcomes cause premature termination of translation and a truncated protein lacking all functional domains.…”

Section: Acd Deficiency Results In Cell Cycle Arrest and Impaired Funmentioning

confidence: 99%

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Hematopoietic stem cells are acutely sensitive to Acd shelterin gene inactivation

Jones¹,

Osawa²,

Regal³

et al. 2013

J. Clin. Invest.

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The shelterin complex plays dual functions in telomere homeostasis by recruiting telomerase and preventing the activation of a DNA damage response at telomeric ends. Somatic stem cells require telomerase activity, as evidenced by progressive stem cell loss leading to bone marrow failure in hereditary dyskeratosis congenita. Recent work demonstrates that dyskeratosis congenita can also arise from mutations in specific shelterin genes, although little is known about shelterin functions in somatic stem cells. We found that mouse hematopoietic stem cells (HSCs) are acutely sensitive to inactivation of the shelterin gene Acd, encoding TPP1. Homozygosity for a hypomorphic acd allele preserved the emergence and expansion of fetal HSCs but led to profoundly defective function in transplantation assays. Upon complete Acd inactivation, HSCs expressed p53 target genes, underwent cell cycle arrest, and were severely depleted within days, leading to hematopoietic failure. TPP1 loss induced increased telomeric fusion events in bone marrow progenitors. However, unlike in epidermal stem cells, p53 deficiency did not rescue TPP1-deficient HSCs, indicating that shelterin dysfunction has unique effects in different stem cell populations. Because the consequences of telomere shortening are progressive and unsynchronized, acute loss of shelterin function represents an attractive alternative for studying telomere crisis in hematopoietic progenitors.

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Section: Acd Deficiency Results In Cell Cycle Arrest and Impaired Funmentioning

confidence: 61%

Section: Acd Deficiency Results In Cell Cycle Arrest and Impaired Funmentioning

confidence: 99%

Hematopoietic stem cells are acutely sensitive to Acd shelterin gene inactivation

Jones¹,

Osawa²,

Regal³

et al. 2013

J. Clin. Invest.

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“…It is located on 16q22.1, a locus previously shown to be deleted in human breast tumors (Roylance et al 1999(Roylance et al , 2006. The protein plays a role in telomere protection (Else et al 2007). ELAC1 and CDH20 are both localized to 18q.…”

Section: Discussionmentioning

confidence: 99%

Identification of metastasis-associated breast cancer genes using a high-resolution whole genome profiling approach

Desouki

Liao

Huang

et al. 2010

J Cancer Res Clin Oncol

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“…Therefore, it was suggested that TPP1 plays an essential organizing function in shelterin, predicting that its deletion would affect TRF1 and TRF2 (25). Furthermore, cytogenetic data on cells from the adrenocortical dysplasia (Acd) mouse strain, which carries a hypomorphic mutation for TPP1 (14), revealed complex chromosomal rearrangements in addition to telomere fusions, leading to the suggestion that TPP1 might have additional telomeric or nontelomeric functions (9).…”

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confidence: 99%

Telomere Protection by TPP1 Is Mediated by POT1a and POT1b

Kibe

Osawa

Keegan

et al. 2010

Molecular and Cellular Biology

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136

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Mammalian telomeres are protected by the shelterin complex, which contains single-stranded telomeric DNA binding proteins (POT1a and POT1b in rodents, POT1 in other mammals). Mouse POT1a prevents the activation of the ATR kinase and contributes to the repression of the nonhomologous end-joining pathway (NHEJ) at newly replicated telomeres. POT1b represses unscheduled resection of the 5-ended telomeric DNA strand, resulting in long 3 overhangs in POT1b KO cells. Both POT1 proteins bind TPP1, forming heterodimers that bind to other proteins in shelterin. Short hairpin RNA (shRNA)-mediated depletion had previously demonstrated that TPP1 contributes to the normal function of POT1a and POT1b. However, these experiments did not establish whether TPP1 has additional functions in shelterin. Here we report on the phenotypes of the conditional deletion of TPP1 from mouse embryo fibroblasts. TPP1 deletion resulted in the release of POT1a and POT1b from chromatin and loss of these proteins from telomeres, indicating that TPP1 is required for the telomere association of POT1a and POT1b but not for their stability. The telomere dysfunction phenotypes associated with deletion of TPP1 were identical to those of POT1a/POT1b DKO cells. No additional telomere dysfunction phenotypes were observed, establishing that the main role of TPP1 is to allow POT1a and POT1b to protect chromosome ends.Mammalian cells solve the chromosome end protection problem through the binding of shelterin to the telomeric TTAGGG repeat arrays at chromosome ends (5). Shelterin contains two double-stranded telomeric DNA binding proteins, TRF1 and TRF2, which both interact with the shelterin subunit TIN2. These three shelterin components, as well as the TRF2 interacting factor Rap1, are abundant, potentially covering the majority of the TTAGGG repeat sequences at chromosome ends (30). TIN2 interacts with the less abundant TPP1/POT1 heterodimers and is thought to facilitate the recruitment of the single-stranded telomeric DNA binding proteins to telomeres (15,21,35).Shelterin represses the four major pathways that threaten mammalian telomeres (6). It prevents activation of the ATM and ATR kinases, which can induce cell cycle arrest in response to double-strand breaks (DSBs). Shelterin also blocks the two major repair pathways that act on DSBs: nonhomologous end joining (NHEJ) and homology-directed repair (HDR). Removal of individual components of shelterin leads to highly specific telomere dysfunction phenotypes, allowing assignment of shelterin functions to each of its components.The POT1 proteins are critical for the repression of ATR signaling (20). Concurrent deletion of POT1a and POT1b from mouse embryo fibroblasts (POT1a/b DKO cells [12]) activates the ATR kinase at most telomeres, presumably because the single-stranded telomeric DNA is exposed to RPA. POT1a/b DKO cells also have a defect in the structure of the telomere terminus, showing extended 3Ј overhangs that are thought to be due to excessive resection of the 5Ј-ended strand in the absence of POT...

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Tpp1/Acd maintains genomic stability through a complex role in telomere protection

Cited by 32 publications

References 47 publications

Hematopoietic stem cells are acutely sensitive to Acd shelterin gene inactivation

Hematopoietic stem cells are acutely sensitive to Acd shelterin gene inactivation

Identification of metastasis-associated breast cancer genes using a high-resolution whole genome profiling approach

Telomere Protection by TPP1 Is Mediated by POT1a and POT1b

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