Oncotarget

Research Papers:

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, Alina Ferster, Armand Biver, Benoit Roch, Nadia Vasquez, Nada Jabado, Francina Langa Vives, Patrick Revy, Jean Soulier and Jean-Pierre de Villartay _

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Oncotarget. 2018; 9:3779-3793. https://doi.org/10.18632/oncotarget.23375

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Abstract

Emilie Lesport1, Alina Ferster2, Armand Biver3, Benoit Roch1, Nadia Vasquez4, Nada Jabado5, Francina Langa Vives6, Patrick Revy1, Jean Soulier4 and Jean-Pierre de Villartay1

1Laboratory “Genome Dynamics in The Immune System”, INSERM UMR1163, Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France

2Departement d’Hémato-Oncologie, Hôpital Universitaire des Enfants Reine Fabiola, Bruxelles, Belgium

3Service de Pédiatrie Générale, Centre Hospitalier De Luxembourg, Luxembourg

4INSERM U944, Institut Universitaire d’Hématologie, Paris, France

5Department of Human Genetics and Department of Experimental Medicine, McGill University, Montreal, Canada

6Centre d’Ingénierie Génétique Murine, Institut Pasteur, Paris, France

Correspondence to:

Jean-Pierre de Villartay, email: [email protected]

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.


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