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Moura I.C.,Laboratory of Excellence GR Ex | Moura I.C.,French Institute of Health and Medical Research | Moura I.C.,Imagine Institute | Moura I.C.,University of Paris Pantheon Sorbonne | And 12 more authors.
Current Opinion in Hematology | Year: 2015

Purpose of review The type 1 transferrin receptor (TfR1) is well known as a key player in erythroid differentiation through its role in iron uptake. Recently, it has been demonstrated that TfR1 could also have signaling functions in erythroid cells. Moreover, the second transferrin receptor, TfR2, whose signaling functions in hepatic cells are well established, was recently shown to be a partner of the erythropoietin receptor (EpoR) and thereby likely to play a role in erythroid differentiation. Recent findings This review reports recent findings regarding the specificities of the regulation of TfR1 expression and iron uptake in erythroblasts. The newly discovered noncanonical actions of TfR1 and TfR2 in erythroid cells are also discussed. Summary Erythrocytes contain more than 60% of the iron of the body and each day, differentiating erythroid cells uptake around 20-mg of iron for heme synthesis. Accordingly, TfR1 is one of the most abundant membrane proteins of the erythroblasts and it is not surprising that specific regulations regarding both its expression and its mechanism of action operate in erythroblasts. The signaling functions of both TfR1 and TfR2 in erythroid cells were unexpected and these recent findings open a new field of research regarding the last steps of erythroid differentiation and their regulation. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Audry J.,Aix - Marseille University | Audry J.,Ligue Nationale Contre le Cancer LNCC Equipe Labellisee | Maestroni L.,Aix - Marseille University | Maestroni L.,Ligue Nationale Contre le Cancer LNCC Equipe Labellisee | And 10 more authors.
EMBO Journal | Year: 2015

Replication protein A (RPA) is a highly conserved heterotrimeric single-stranded DNA-binding protein involved in DNA replication, recombination, and repair. In fission yeast, the Rpa1-D223Y mutation provokes telomere shortening. Here, we show that this mutation impairs lagging-strand telomere replication and leads to the accumulation of secondary structures and recruitment of the homologous recombination factor Rad52. The presence of these secondary DNA structures correlates with reduced association of shelterin subunits Pot1 and Ccq1 at telomeres. Strikingly, heterologous expression of the budding yeast Pif1 known to efficiently unwind G-quadruplex rescues all the telomeric defects of the D223Y cells. Furthermore, in vitro data show that the identical D to Y mutation in human RPA specifically affects its ability to bind G-quadruplex. We propose that RPA prevents the formation of G-quadruplex structures at lagging-strand telomeres to promote shelterin association and facilitate telomerase action at telomeres. Synopsis RPA prevents (or unwinds) the formation of G-rich structures such as G-quadruplexes at lagging-strand telomeres during replication to ensure functional shelterin association. The mutation D223Y in Rpa1 leads to telomere shortening and replication defects at lagging-stand telomeres. Homologous recombination is critical to sustain viability of the Rpa1-D223Y mutant. Over-expression of Pif1-family helicases restores telomeric defects seen in Rpa1-D223Y mutant. The corresponding mutation D to Y in human RPA1 affects single-stranded DNA binding activity of hRPA complex. The single-stranded DNA binding protein RPA promotes telomere maintenance by inhibiting accumulation of G-quadruplex structures at lagging-strand telomeres. © 2015 The Authors.

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