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Cell Death Dis. 2014 Mar 20;5:e1130. doi: 10.1038/cddis.2014.99.

Homozygous mutation of MTPAP causes cellular radiosensitivity and persistent DNA double-strand breaks.

Author information

1
1] UCLA Department of Pathology and Laboratory Medicine, MacDonald Research Laboratories, Los Angeles, CA, USA [2] UCLA Biomedical Physics Interdepartmental Graduate Program, Los Angeles, CA, USA.
2
UCLA Department of Pathology and Laboratory Medicine, MacDonald Research Laboratories, Los Angeles, CA, USA.
3
Department of Public Health Sciences, Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
4
Genetics Institute, University of Florida, Gainesville, FL, USA.
5
UCLA Department of Pediatrics, Los Angeles, CA, USA.
6
Carle Physician Group, Urbana, IL, USA.
7
1] UCLA Department of Pathology and Laboratory Medicine, MacDonald Research Laboratories, Los Angeles, CA, USA [2] UCLA Biomedical Physics Interdepartmental Graduate Program, Los Angeles, CA, USA [3] UCLA Department of Human Genetics, Los Angeles, CA, USA.
8
1] Genetics Institute, University of Florida, Gainesville, FL, USA [2] Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, USA.

Abstract

The study of rare human syndromes characterized by radiosensitivity has been instrumental in identifying novel proteins and pathways involved in DNA damage responses to ionizing radiation. In the present study, a mutation in mitochondrial poly-A-polymerase (MTPAP), not previously recognized for its role in the DNA damage response, was identified by exome sequencing and subsequently associated with cellular radiosensitivity. Cell lines derived from two patients with the homozygous MTPAP missense mutation were radiosensitive, and this radiosensitivity could be abrogated by transfection of wild-type mtPAP cDNA into mtPAP-deficient cell lines. Further analysis of the cellular phenotype revealed delayed DNA repair, increased levels of DNA double-strand breaks, increased reactive oxygen species (ROS), and increased cell death after irradiation (IR). Pre-IR treatment of cells with the potent anti-oxidants, α-lipoic acid and n-acetylcysteine, was sufficient to abrogate the DNA repair and clonogenic survival defects. Our results firmly establish that mutation of the MTPAP gene results in a cellular phenotype of increased DNA damage, reduced repair kinetics, increased cell death by apoptosis, and reduced clonogenic survival after exposure to ionizing radiation, suggesting a pathogenesis that involves the disruption of ROS homeostasis.

PMID:
24651433
PMCID:
PMC3973239
DOI:
10.1038/cddis.2014.99
[Indexed for MEDLINE]
Free PMC Article
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