Reduced recruitment of 53BP1 during interstrand crosslink repair is associated with genetically inherited attenuation of mitomycin C sensitivity in a family with Fanconi anemia

// Emilie Lesport 1 , Alina Ferster 2 , Armand Biver 3 , Benoit Roch 1 , Nadia Vasquez 4 , Nada Jabado 5 , Francina Langa Vives 6 , Patrick Revy 1 , Jean Soulier 4 and Jean-Pierre de Villartay 1 1 Laboratory “Genome Dynamics in The Immune System”, INSERM UMR1163, Universite Paris Descartes Sorbonne Paris Cite, Institut Imagine, Paris, France 2 Departement d’Hemato-Oncologie, Hopital Universitaire des Enfants Reine Fabiola, Bruxelles, Belgium 3 Service de Pediatrie Generale, Centre Hospitalier De Luxembourg, Luxembourg 4 INSERM U944, Institut Universitaire d’Hematologie, Paris, France 5 Department of Human Genetics and Department of Experimental Medicine, McGill University, Montreal, Canada 6 Centre d’Ingenierie Genetique Murine, Institut Pasteur, Paris, France Correspondence to: Jean-Pierre de Villartay, email: devillartay@gmail.com Keywords: Fanconi anemia; DNA interstrand crosslinks; DNA double strand break repair; 53BP1; ATM Received: May 30, 2017      Accepted: November 28, 2017      Published: December 17, 2017 ABSTRACT The Fanconi anemia (FA) pathway is implicated in the repair of DNA interstrand crosslinks (ICL). In this process, it has been shown that FA factors regulate the choice for DNA double strand break repair towards homologous recombination (HR). As this mechanism is impaired in FA deficient cells exposed to crosslinking agents, an inappropriate usage of non-homologous end joining (NHEJ) leads to the accumulation of toxic chromosomal abnormalities. We studied a family with two FANCG patients and found a genetically inherited attenuation of mitomycin C sensitivity resulting in-vitro in an attenuated phenotype for one patient or in increased resistance for two healthy relatives. A heterozygous mutation in ATM was identified in these 3 subjects but was not directly linked to the observed phenotype. However, the attenuation of ICL sensitivity was associated with a reduced recruitment of 53BP1 during the course of ICL repair, and increased HR levels. These results further demonstrate the importance of favoring HR over NHEJ for the survival of cells challenged with ICLs.