title: ERCC6L2 mutations link a distinct bone-marrow-failure syndrome to DNA repair and mitochondrial function.
abstract: Exome sequencing was performed in three index cases with bone marrow failure and neurological dysfunction and whose parents are first-degree cousins. Homozygous truncating mutations were identified in ERCC6L2 in two of the individuals. Both of these mutations affect the subcellular localization and stability of ERCC6L2. We show here that knockdown of ERCC6L2 in human A549 cells significantly reduced their viability upon exposure to the DNA-damaging agents mitomycin C and Irofulven, but not etoposide and camptothecin, suggesting a role in nucleotide excision repair. ERCC6L2-knockdown cells also displayed H2AX phosphorylation, which significantly increased upon genotoxic stress, suggesting an early DNA-damage response. Intriguingly, ERCC6L2 was seen to translocate to the mitochondria and the nucleus in response to DNA damage, and ERCC6L2 knockdown induced intracellular reactive oxygen species (ROS). Treatment with the ROS scavenger N-acetyl cysteine attenuated the Irofulven-induced cytotoxicity in ERCC6L2-knockdown cells and abolished ERCCGL2 traffic to the mitochondria and nucleus in response to this DNA-damaging agent. Collectively, these observations identify a distinct bone-marrow-failure syndrome due to mutations in ERCC6L2, a gene implicated in DNA repair and mitochondrial function.
authors: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors: Hemanth
authors: H
authors: Tummala
authors: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors: Michael
authors: M
authors: Kirwan
authors: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors: Amanda J
authors: AJ
authors: Walne
authors: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK; Barts Health NHS Trust, London E1 1BB, UK.
authors: Upal
authors: U
authors: Hossain
authors: Department of Haematology, University Hospital, Coventry CV2 2DX, UK.
authors: Nicholas
authors: N
authors: Jackson
authors: Institute of Pediatric Hematology and Oncology, Lyon I University, Lyon 69008, France.
authors: Corinne
authors: C
authors: Pondarre
authors: University College London Genetics Institute, London WC1E 6BT, UK.
authors: Vincent
authors: V
authors: Plagnol
authors: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK. Electronic address: t.vulliamy@qmul.ac.uk.
authors: Tom
authors: T
authors: Vulliamy
authors: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK; Barts Health NHS Trust, London E1 1BB, UK.
authors: Inderjeet
authors: I
authors: Dokal
mesh_terms: D000111:Acetylcysteine / Q000378:metabolism; D000741:Anemia, Aplastic; D001855:Bone Marrow Diseases; D000080983:Bone Marrow Failure Disorders; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004265:DNA Helicases / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006457:Hemoglobinuria, Paroxysmal / Q000235:genetics*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics*; D016685:Mitomycin / Q000633:toxicity; D009154:Mutation; D010375:Pedigree; D010766:Phosphorylation; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes / Q000633:toxicity
chemical_list: D006657:Histones; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; D016685:Mitomycin; C102714:irofulven; D004265:DNA Helicases; C587425:ERCC6L2 protein, human; D000111:Acetylcysteine