2. Academic Validation
  3. ERCC6L2 mutations link a distinct bone-marrow-failure syndrome to DNA repair and mitochondrial function

ERCC6L2 mutations link a distinct bone-marrow-failure syndrome to DNA repair and mitochondrial function

  • Am J Hum Genet. 2014 Feb 6;94(2):246-56. doi: 10.1016/j.ajhg.2014.01.007.
Hemanth Tummala 1,  Michael Kirwan 1,  Amanda J Walne 1,  Upal Hossain 2,  Nicholas Jackson 3,  Corinne Pondarre 4,  Vincent Plagnol 5,  Tom Vulliamy 6,  Inderjeet Dokal 2
Affiliations

Affiliations

  • 1 Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
  • 2 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.
  • 3 Department of Haematology, University Hospital, Coventry CV2 2DX, UK.
  • 4 Institute of Pediatric Hematology and Oncology, Lyon I University, Lyon 69008, France.
  • 5 University College London Genetics Institute, London WC1E 6BT, UK.
  • 6 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.
PMID: 24507776 DOI: 10.1016/j.ajhg.2014.01.007
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.

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