Parent Category: Laboratoires Published: Thursday, 16 February 2012

Genome Surveillance and Stability

PHOTO MAIORANO

Domenico MAIORANO

 

 IGH - UMR 9004

 141, rue de la Cardonille, 34396 Montpellier

 

Phone: +33 4 34 35 99 73

Email: domenico.maiorano@igh.cnrs.fr

       

Website

 

 

 

 

The major goal of the team is to understand the molecular mechanisms that govern the activation of the DNA replication checkpoint (Recolin et al., 2012; Recolin and Maiorano, 2012; Bétous et al., 2013), and the DNA damage response (Tsanov et al., 2013), in somatic cells as well as during early development, when checkpoints are relaxed. Our laboratory has very recently unveiled the molecular bases of checkpoint regulation in mouse embryonic stem cells (Van der Laan et al., 2013). We have identified a novel pathway comprising Esrrb-Dub3-Cdc25A-Cdk2, that links maintenance of pluripotency, through EsrrB, to suppression of the G1/S checkpoint by constitutive inactivation of the Cdk2 kinase. We have shown that Dub3 is a new, highly specific marker of ES cells, essential for maintenance of pluripotency, whose expression is very rapidly downregulated during differentiation, much faster than the well-known embryonic stem cells marker Oct4. We have also shown that cell cycle remodelling of ES cells is essential for generation of viable, differentiated cells. We are also seeking new genes implicated in the DNA damage response. By means of in vitro and in silico screens we have identified several genes as potential new candidates implicated in the DNA damage response whose characterization is currently under way.

 

One of these is the Ddx19 RNA helicase, previously implicated in the export of the mRNA from the nucleus into the cytoplasm. We have shown that Ddx19 translocates from the nuclear peryphery into the nuclus upon DNA damage (Figure 4). We have also unveiled a novel nuclear function for this enzyme in the resolution of aberrant RNA:DNA hybrid structures formed upon conflicts between replication and transcription, the so called R-loops (Hodroj et al., EMBO J 2017). We are now in the process of understanding the molecular basis of this novel function for the Ddx19 helicase.

 

Keywords: DNA damage/chromatin/in vitro systems/single-stranded DNA/Xenopus

 

 

Main publications :

 

  • Hodroj D, Recolin B, Serhal K, Martinez S, Tsanov N, Abou Merhi R, Maiorano D. An ATR-dependent function for the Ddx19 RNA helicase in nuclear R-loop metabolism. EMBO J. 2017 May 2;36(9):1182-1198.
  • Kermi C, Prieto S, van der Laan S, Tsanov N, Recolin B, Uro-Coste E, Delisle MB, Maiorano D. RAD18 Is a Maternal Limiting Factor Silencing the UV-Dependent DNA Damage Checkpoint in Xenopus Embryos. Dev Cell. 2015 Aug 10;34(3):364-72.
  • Van der Laan S, Golfetto E, Vanacker JM, MAIORANO D. Cell cycle-dependent expression of Dub3, Nanog and the p160 family of nuclear receptor coactivators (NCoAs) in mouse embryonic stem cells. PLoS One. 2014 Apr 2;9(4):e93663.
  • Tsanov N, Coulombe P, Van der Laan S, Hodroj D, and Maiorano D. PIP degron proteins, substrates of CRL4Cdt2, and not PIP boxes, interfere with DNA polymerase η and κ focus formation on UV damage .Nucleic Acids Res. (in press).
  • Van der Laan S, Tsanov N, Crozet C, Maiorano D. High Dub3 expression in mouse ESCs couples the G1/S checkpoint to pluripotency. Mol Cell. 2013 Nov 7;52(3):366-79.
  • Maiorano D, Hoffmann JS. Pol κ in replication checkpoint. Cell Cycle. 2013 Dec 15;12(24):3713-4. d
  • Bétous R, Pillaire MJ, Pierini L, van der Laan S, Recolin B, Ohl-Séguy E, Guo C, Niimi N, Grúz P, Nohmi T, Friedberg E, Cazaux C, Maiorano D*, Hoffmann JS*. DNA polymerase κ-dependent DNA synthesis at stalled replication forks is important for CHK1 activation. EMBO J. 2013 Jul 31;32(15):2172-85. *corresponding authors.
  • Recolin B, Maiorano D. Implication of RPA32 phosphorylation in S-phase checkpoint signalling at replication forks stalled with aphidicolin in Xenopus egg extracts. Biochem Biophys Res Commun. 2012 Nov 2;427(4):785-9.
  • Recolin B, Van der Laan S, Maiorano D. Role of replication protein A as sensor in activation of the S-phase checkpoint in Xenopus egg extracts. Nucleic Acids Res. 2012 Apr;40(8):3431-42.
  • Lévy N, Oehlmann M, Delalande F, Nasheuer HP, Van Dorsselaer A, Schreiber V, de Murcia G, Ménissier-de Murcia J, Maiorano D, Bresson A. XRCC1 interacts withthe p58 subunit of DNA Pol alpha-primase and may coordinate DNA repair and replication during S phase. Nucleic Acids Res. 2009 Jun;37(10):3177-88. * corresponding authors

 

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