AKTIP/Ft1, a New Shelterin-Interacting Factor Required for Telomere Maintenance.
Type
ArticleAuthors
Burla, RominaCarcuro, Mariateresa
Raffa, Grazia D
Galati, Alessandra
Raimondo, Domenico
Rizzo, Angela
La Torre, Mattia
Micheli, Emanuela
Ciapponi, Laura
Cenci, Giovanni
Cundari, Enrico
Musio, Antonio
Biroccio, Annamaria
Cacchione, Stefano
Gatti, Maurizio
Saggio, Isabella
KAUST Grant Number
KUK-I1-012-43Date
2015-06-25Permanent link to this record
http://hdl.handle.net/10754/596764
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Show full item recordAbstract
Telomeres are nucleoprotein complexes that protect the ends of linear chromosomes from incomplete replication, degradation and detection as DNA breaks. Mammalian telomeres are protected by shelterin, a multiprotein complex that binds the TTAGGG telomeric repeats and recruits a series of additional factors that are essential for telomere function. Although many shelterin-associated proteins have been so far identified, the inventory of shelterin-interacting factors required for telomere maintenance is still largely incomplete. Here, we characterize AKTIP/Ft1 (human AKTIP and mouse Ft1 are orthologous), a novel mammalian shelterin-bound factor identified on the basis of its homology with the Drosophila telomere protein Pendolino. AKTIP/Ft1 shares homology with the E2 variant ubiquitin-conjugating (UEV) enzymes and has been previously implicated in the control of apoptosis and in vesicle trafficking. RNAi-mediated depletion of AKTIP results in formation of telomere dysfunction foci (TIFs). Consistent with these results, AKTIP interacts with telomeric DNA and binds the shelterin components TRF1 and TRF2 both in vivo and in vitro. Analysis of AKTIP- depleted human primary fibroblasts showed that they are defective in PCNA recruiting and arrest in the S phase due to the activation of the intra S checkpoint. Accordingly, AKTIP physically interacts with PCNA and the RPA70 DNA replication factor. Ft1-depleted p53-/- MEFs did not arrest in the S phase but displayed significant increases in multiple telomeric signals (MTS) and sister telomere associations (STAs), two hallmarks of defective telomere replication. In addition, we found an epistatic relation for MST formation between Ft1 and TRF1, which has been previously shown to be required for replication fork progression through telomeric DNA. Ch-IP experiments further suggested that in AKTIP-depleted cells undergoing the S phase, TRF1 is less tightly bound to telomeric DNA than in controls. Thus, our results collectively suggest that AKTIP/Ft1 works in concert with TRF1 to facilitate telomeric DNA replication.Citation
Burla R, Carcuro M, Raffa GD, Galati A, Raimondo D, et al. (2015) AKTIP/Ft1, a New Shelterin-Interacting Factor Required for Telomere Maintenance. PLOS Genetics 11: e1005167. Available: http://dx.doi.org/10.1371/journal.pgen.1005167.Sponsors
This work has been supported by Grants EU FP7 BrainCAV (n. 222992) and EU FP7 Brainvectors (n. 286071) to IS, AIRC (n. 10793) to MG and KAUST Award (KUK-I1-012-43) to DR. AR is a recipient of fellowships from Umberto Veronesi Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Publisher
Public Library of Science (PLoS)Journal
PLOS GeneticsPubMed ID
26110528PubMed Central ID
PMC4481533ae974a485f413a2113503eed53cd6c53
10.1371/journal.pgen.1005167
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