AKTIP/Ft1, a New Shelterin-Interacting Factor Required for Telomere Maintenance.

Handle URI:
http://hdl.handle.net/10754/596764
Title:
AKTIP/Ft1, a New Shelterin-Interacting Factor Required for Telomere Maintenance.
Authors:
Burla, Romina; Carcuro, 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
Abstract:
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.
Publisher:
Public Library of Science (PLoS)
Journal:
PLOS Genetics
KAUST Grant Number:
KUK-I1-012-43
Issue Date:
25-Jun-2015
DOI:
10.1371/journal.pgen.1005167
PubMed ID:
26110528
PubMed Central ID:
PMC4481533
Type:
Article
ISSN:
1553-7404
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.
Appears in Collections:
Publications Acknowledging KAUST Support

Full metadata record

DC FieldValue Language
dc.contributor.authorBurla, Rominaen
dc.contributor.authorCarcuro, Mariateresaen
dc.contributor.authorRaffa, Grazia Den
dc.contributor.authorGalati, Alessandraen
dc.contributor.authorRaimondo, Domenicoen
dc.contributor.authorRizzo, Angelaen
dc.contributor.authorLa Torre, Mattiaen
dc.contributor.authorMicheli, Emanuelaen
dc.contributor.authorCiapponi, Lauraen
dc.contributor.authorCenci, Giovannien
dc.contributor.authorCundari, Enricoen
dc.contributor.authorMusio, Antonioen
dc.contributor.authorBiroccio, Annamariaen
dc.contributor.authorCacchione, Stefanoen
dc.contributor.authorGatti, Maurizioen
dc.contributor.authorSaggio, Isabellaen
dc.date.accessioned2016-02-21T08:50:11Zen
dc.date.available2016-02-21T08:50:11Zen
dc.date.issued2015-06-25en
dc.identifier.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.en
dc.identifier.issn1553-7404en
dc.identifier.pmid26110528en
dc.identifier.doi10.1371/journal.pgen.1005167en
dc.identifier.urihttp://hdl.handle.net/10754/596764en
dc.description.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.en
dc.description.sponsorshipThis 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.en
dc.publisherPublic Library of Science (PLoS)en
dc.rightsThis 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 crediteden
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleAKTIP/Ft1, a New Shelterin-Interacting Factor Required for Telomere Maintenance.en
dc.typeArticleen
dc.identifier.journalPLOS Geneticsen
dc.identifier.pmcidPMC4481533en
dc.contributor.institutionDipartimento di Biologia e Biotecnologie, Sapienza-Università di Roma, Roma, Italy; Istituto Pasteur Fondazione Cenci Bolognetti, Sapienza-Università di Roma, Roma, Italy.en
dc.contributor.institutionDipartimento di Fisica, Sapienza-Università di Roma, Roma, Italy.en
dc.contributor.institutionIstituto Nazionale Tumori Regina Elena, Rome, Italy.en
dc.contributor.institutionIstituto di Biologia e Patologia Molecolari del CNR, Sapienza-Università di Roma, Roma, Italy.en
dc.contributor.institutionIstituto di Ricerca Genetica e Biomedica del CNR, Pisa, and Istituto Toscano Tumori, Firenze, Italy.en
dc.contributor.institutionDipartimento di Biologia e Biotecnologie, Sapienza-Università di Roma, Roma, Italy; Istituto Pasteur Fondazione Cenci Bolognetti, Sapienza-Università di Roma, Roma, Italy; Istituto di Biologia e Patologia Molecolari del CNR, Sapienza-Università di Roma, Roma, Italy.en
kaust.grant.numberKUK-I1-012-43en

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