AKTIP/Ft1, a New Shelterin-Interacting Factor Required for Telomere Maintenance.
Raffa, Grazia D
La Torre, Mattia
KAUST Grant NumberKUK-I1-012-43
Permanent link to this recordhttp://hdl.handle.net/10754/596764
MetadataShow full item record
AbstractTelomeres 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.
CitationBurla 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.
SponsorsThis 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.
PublisherPublic Library of Science (PLoS)
PubMed Central IDPMC4481533
CollectionsPublications Acknowledging KAUST Support
Except where otherwise noted, this item's license is described as This is an open access article distributed under the terms of the , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
- Telomere-bound TRF1 and TRF2 stall the replication fork at telomeric repeats.
- Authors: Ohki R, Ishikawa F
- Issue date: 2004
- Post-translational modifications of TRF1 and TRF2 and their roles in telomere maintenance.
- Authors: Walker JR, Zhu XD
- Issue date: 2012 Jun
- TRF1 negotiates TTAGGG repeat-associated replication problems by recruiting the BLM helicase and the TPP1/POT1 repressor of ATR signaling.
- Authors: Zimmermann M, Kibe T, Kabir S, de Lange T
- Issue date: 2014 Nov 15
- Molecular recognition in complexes of TRF proteins with telomeric DNA.
- Authors: Wieczór M, Tobiszewski A, Wityk P, Tomiczek B, Czub J
- Issue date: 2014
- The telomeric protein AKTIP interacts with A- and B-type lamins and is involved in regulation of cellular senescence.
- Authors: Burla R, Carcuro M, Torre ML, Fratini F, Crescenzi M, D'Apice MR, Spitalieri P, Raffa GD, Astrologo L, Lattanzi G, Cundari E, Raimondo D, Biroccio A, Gatti M, Saggio I
- Issue date: 2016 Aug