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Journal article
Fanconi anemia group J mutation abolishes its DNA repair function by uncoupling DNA translocation from helicase activity or disruption of protein-DNA complexes
Blood, v 116(19), pp 3780-3791
11 Nov 2010
PMID: 20639400
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Fanconi anemia (FA) is a genetic disease characterized by congenital abnormalities, bone marrow failure, and susceptibility to leukemia and other cancers. FANCJ, one of 13 genes linked to FA, encodes a DNA helicase proposed to operate in homologous recombination repair and replicational stress response. The pathogenic FANCJ-A349P amino acid substitution resides immediately adjacent to a highly conserved cysteine of the iron-sulfur domain. Given the genetic linkage of the FANCJ-A349P allele to FA, we investigated the effect of this particular mutation on the biochemical and cellular functions of the FANCJ protein. Purified recombinant FANCJ-A349P protein had reduced iron and was defective in coupling adenosine triphosphate (ATP) hydrolysis and translocase activity to unwinding forked duplex or G-quadruplex DNA substrates or disrupting protein-DNA complexes. The FANCJ-A349P allele failed to rescue cisplatin or telomestatin sensitivity of a FA-J null cell line as detected by cell survival or gamma-H2AX foci formation. Furthermore, expression of FANCJ-A349P in a wild-type background exerted a dominant-negative effect, indicating that the mutant protein interferes with normal DNA metabolism. The ability of FANCJ to use the energy from ATP hydrolysis to produce the force required to unwind DNA or destabilize protein bound to DNA is required for its role in DNA repair. (Blood. 2010;116(19):3780-3791)
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- Title
- Fanconi anemia group J mutation abolishes its DNA repair function by uncoupling DNA translocation from helicase activity or disruption of protein-DNA complexes
- Creators
- Yuliang Wu - Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health (NIH), National Institutes of Health Biomedical Research Center, Baltimore, MD;Joshua A. Sommers - Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health (NIH), National Institutes of Health Biomedical Research Center, Baltimore, MD;Avvaru N. Suhasini - Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health (NIH), National Institutes of Health Biomedical Research Center, Baltimore, MD;Thomas Leonard - National Institute of Diabetes and Digestive and Kidney DiseasesJulianna S. Deakyne - Department of Biochemistry and Molecular Biology; Drexel University College of Medicine; Philadelphia PAAlexander V. Mazin - Drexel UniversityKazuo Shin-ya - National Institute of Advanced Industrial Science and TechnologyHiroyuki Kitao - Kyoto UniversityRobert M. Brosh - Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health (NIH), National Institutes of Health Biomedical Research Center, Baltimore, MD;
- Publication Details
- Blood, v 116(19), pp 3780-3791
- Publisher
- Amer Soc Hematology
- Number of pages
- 12
- Grant note
- R56CA100839 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) Fanconi Anemia Research Fund CA100839 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 1054-09 / Leukemia & Lymphoma Society; Leukemia and Lymphoma Society ZIAAG000752 / NATIONAL INSTITUTE ON AGING; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) National Institutes of Health, National Institute on Aging, and National Institute of Diabetes and Digestive and Kidney Diseases; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK); NIH National Institute on Aging (NIA)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000284110400018
- Scopus ID
- 2-s2.0-77958512174
- Other Identifier
- 991019168683104721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Hematology