A Role for BLM in Double-Strand Break Repair Pathway Choice: Prevention of CtIP/Mre11-Mediated Alternative Nonhomologous End-Joining
Anastazja Grabarz,
Josée Guirouilh-Barbat,
Aurélia Barascu,
Gaëlle Pennarun,
Diane Genet,
Emilie Rass,
Susanne M. Germann,
Pascale Bertrand,
Ian D. Hickson,
Bernard S. Lopez
Affiliations
Anastazja Grabarz
CNRS UMR217, CEA, DSV, Institut de Radiobiologie Cellulaire et Moléculaire, 18 Route du Panorama, Fontenay aux Roses F-92265, France
Josée Guirouilh-Barbat
Université Paris Sud, CNRS UMR 8200, Institut de Cancérologie Gustave-Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France
Aurélia Barascu
Université Paris Sud, CNRS UMR 8200, Institut de Cancérologie Gustave-Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France
Gaëlle Pennarun
CNRS UMR217, CEA, DSV, Institut de Radiobiologie Cellulaire et Moléculaire, 18 Route du Panorama, Fontenay aux Roses F-92265, France
Diane Genet
CNRS UMR217, CEA, DSV, Institut de Radiobiologie Cellulaire et Moléculaire, 18 Route du Panorama, Fontenay aux Roses F-92265, France
Emilie Rass
CNRS UMR217, CEA, DSV, Institut de Radiobiologie Cellulaire et Moléculaire, 18 Route du Panorama, Fontenay aux Roses F-92265, France
Susanne M. Germann
Nordea Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen N, Denmark
Pascale Bertrand
CNRS UMR217, CEA, DSV, Institut de Radiobiologie Cellulaire et Moléculaire, 18 Route du Panorama, Fontenay aux Roses F-92265, France
Ian D. Hickson
Nordea Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen N, Denmark
Bernard S. Lopez
Université Paris Sud, CNRS UMR 8200, Institut de Cancérologie Gustave-Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France
The choice of the appropriate double-strand break (DSB) repair pathway is essential for the maintenance of genomic stability. Here, we show that the Bloom syndrome gene product, BLM, counteracts CtIP/MRE11-dependent long-range deletions (>200 bp) generated by alternative end-joining (A-EJ). BLM represses A-EJ in an epistatic manner with 53BP1 and RIF1 and is required for ionizing-radiation-induced 53BP1 focus assembly. Conversely, in the absence of 53BP1 or RIF1, BLM promotes formation of A-EJ long deletions, consistent with a role for BLM in DSB end resection. These data highlight a dual role for BLM that influences the DSB repair pathway choice: (1) protection against CtIP/MRE11 long-range deletions associated with A-EJ and (2) promotion of DNA resection. These antagonist roles can be regulated, according to cell-cycle stage, by interacting partners such as 53BP1 and TopIII, to avoid unscheduled resection that might jeopardize genome integrity.
