A Role for BLM in Double-Strand Break Repair Pathway Choice: Prevention of CtIP/Mre11-Mediated Alternative Nonhomologous End-Joining

• Main Authors: Anastazja Grabarz, Josée Guirouilh-Barbat, Aurélia Barascu, Gaëlle Pennarun, Diane Genet, Emilie Rass, Susanne M. Germann, Pascale Bertrand, Ian D. Hickson, Bernard S. Lopez
• Format: Article
• Language: English
• Published: Elsevier 2013-10-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124713004750

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.