TRF1 phosphorylation on T271 modulates telomerase-dependent telomere length maintenance as well as the formation of ALT-associated PML bodies

Ho, Angus; Wilson, Florence R.; Peragine, Stephanie L.; Jeyanthan, Kajaparan; Mitchell, Taylor R. H.; Zhu, Xu-Dong

doi:10.1038/srep36913

Cited by 10 publications

(11 citation statements)

References 32 publications

(74 reference statements)

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“…In particular, by using in vitro phosphorylation assays, we identify Threonine 330 (T330) and Threonine 248 (T248) as bona fide AKT1 phosphorylation sites in mouse TRF1. In addition, we show that AKT1 also phosphorylates mouse TRF1 at Serine 344, which is the analogous site to human TRF1 residues Threonine 271 and Threonine 273, recently shown to be necessary for TRF1 binding to telomeres 24 , 81 . Furthermore, we show that substitution of these residues in mouse TRF1 to non-phosphorylatable alanine residues in S344A and T330A mutants results in significantly reduced levels of in vitro AKT1-dependent TRF1 phosphorylation.…”

Section: Discussionmentioning

confidence: 54%

Modulation of telomere protection by the PI3K/AKT pathway

et al. 2017

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Telomeres and the insulin/PI3K pathway are considered hallmarks of aging and cancer. Here, we describe a role for PI3K/AKT in the regulation of TRF1, an essential component of the shelterin complex. PI3K and AKT chemical inhibitors reduce TRF1 telomeric foci and lead to increased telomeric DNA damage and fragility. We identify the PI3Kα isoform as responsible for this TRF1 inhibition. TRF1 is phosphorylated at different residues by AKT and these modifications regulate TRF1 protein stability and TRF1 binding to telomeric DNA in vitro and are important for in vivo TRF1 telomere location and cell viability. Patient-derived breast cancer PDX mouse models that effectively respond to a PI3Kα specific inhibitor, BYL719, show decreased TRF1 levels and increased DNA damage. These findings functionally connect two of the major pathways for cancer and aging, telomeres and the PI3K pathway, and pinpoint PI3K and AKT as novel targets for chemical modulation of telomere protection.

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Section: Discussionmentioning

confidence: 54%

Modulation of telomere protection by the PI3K/AKT pathway

et al. 2017

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“…IF and IF-FISH were carried out essentially as described (Ho et al, 2016;Wilson et al, 2016). For IF except for POLD3 staining, cells seeded on coverslips were fixed directly in PBS-buffered 3% paraformaldehyde.…”

Section: If and Fishmentioning

confidence: 99%

“…Gels were run for 20 h at 5.4 V/cm at a constant pulse time of 5 s using a CHEF DR-II pulsed-field apparatus (Bio-Rad). C-circle amplification assays were performed as described (Ho et al, 2016). Following heat inactivation of φ29 at 65°C for 20 min, samples were loaded on the dot blots.…”

Section: Telomere Length Analysis and C-circle Amplication Assaysmentioning

confidence: 99%

CSB cooperates with SMARCAL1 to maintain telomere stability in ALT cells

Feng

Batenburg

Walker

et al. 2020

Journal of Cell Science

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Elevated replication stress is evident at telomeres of about 10-15% of cancer cells, which maintain their telomeres via a homologous recombination (HR)-based mechanism, referred to as alternative lengthening of telomeres (ALT). How ALT cells resolve replication stress to support their growth remains incompletely characterized. Here, we report that CSB (also known as ERCC6) promotes recruitment of HR repair proteins (MRN, BRCA1, BLM and RPA32) and POLD3 to ALT telomeres, a process that requires the ATPase activity of CSB and is controlled by ATM-and CDK2-dependent phosphorylation. Loss of CSB stimulates telomeric recruitment of MUS81 and SLX4, components of the structure-specific MUS81-EME1-SLX1-SLX4 (MUS-SLX) endonuclease complex, suggesting that CSB restricts MUS-SLX-mediated processing of stalled forks at ALT telomeres. Loss of CSB coupled with depletion of SMARCAL1, a chromatin remodeler implicated in catalyzing regression of stalled forks, synergistically promotes not only telomeric recruitment of MUS81 but also the formation of fragile telomeres, the latter of which is reported to arise from fork stalling. These results altogether suggest that CSB-mediated HR repair and SMARCAL1-mediated fork regression cooperate to prevent stalled forks from being processed into fragile telomeres in ALT cells.

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“…ALT are characterized by telomere associated PML bodies (called APBs) containing HR proteins, sheltering factors and heterochromatin associated proteins such as HP1 [ 30 , 31 ]. Moreover, a specific phosphorylated isoform of TRF1 has been found associated with and required for APBs formation [ 32 , 33 ]. Therefore, chromatin modification appears to be one of the key factors determining the choice between TA and ALT.…”

Section: Molecular Mechanisms Of Alt Activationmentioning

confidence: 99%

Diagnosis and treatment of ALT tumors: is Trabectedin a new therapeutic option?

Pompili

Leonetti²,

Biroccio³

et al. 2017

J Exp Clin Cancer Res

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Telomeres are specialized nucleoprotein structures responsible for protecting chromosome ends in order to prevent the loss of genomic information. Telomere maintenance is required for achieving immortality by neoplastic cells. While most cancer cells rely on telomerase re-activation for linear chromosome maintenance and sustained proliferation, a significant population of cancers (10–15%) employs telomerase-independent strategies, collectively referred to as Alternative Lengthening of Telomeres (ALT). ALT mechanisms involve different types of homology-directed telomere recombination and synthesis. These processes are facilitated by loss of the ATRX or DAXX chromatin-remodeling factors and by abnormalities of the telomere nucleoprotein architecture. Although the functional consequences of telomerase and ALT up-regulation are similar in that they both prevent overall telomere shortening in tumors, these telomere maintenance mechanisms (TMMs) differ in several aspects which may account for their differential prognostic significance and response to therapy in various tumor types. Therefore, reliable methods for detecting telomerase activity and ALT are likely to become an important pre-requisite for the use of treatments targeting one or other of these mechanisms. However, the question whether ALT presence can confer sensitivity to rationally designed anti-cancer therapies is still open. Here we review the latest discoveries in terms of mechanisms of ALT activation and maintenance in human tumors, methods for ALT identification in cell lines and human tissues and biomarkers validation. Then, original results on sensitivity to rational based pre-clinical and clinical anti-tumor drugs in ALT vs hTERT positive cells will be presented.

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TRF1 phosphorylation on T271 modulates telomerase-dependent telomere length maintenance as well as the formation of ALT-associated PML bodies

Cited by 10 publications

References 32 publications

Modulation of telomere protection by the PI3K/AKT pathway

Modulation of telomere protection by the PI3K/AKT pathway

CSB cooperates with SMARCAL1 to maintain telomere stability in ALT cells

Diagnosis and treatment of ALT tumors: is Trabectedin a new therapeutic option?

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