Journal
PLOS ONE
Volume 6, Issue 3, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0017151
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Funding
- NCI [5R01CA058320-15]
- NIH [5F32GM069297]
- California Institute of Regenerative Medicine (CIRM)
- Don Cleveland in the Ludwig Institute for Cancer Research
- UCSD Neuroscience Microscopy Shared Facility [P30 NS047101]
- UCSD Cancer Center Specialized Support [P30 CA23100]
- Research Council of Norway
- National Programme for Research in Functional Genomics in Norway (FUGE)
- Norwegian Cancer Association
- Cancer Fund at St. Olavs Hospital, Trondheim
- Svanhild
- Arne Must Fund for Medical Research
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Uracil is removed from DNA by the conserved enzyme Uracil DNA N-glycosylase (UNG). Previously, we observed that inhibiting UNG in Xenopus egg extracts blocked assembly of CENP-A, a histone H3 variant. CENP-A is an essential protein in all species, since it is required for chromosome segregation during mitosis. Thus, the implication of UNG in CENP-A assembly implies that UNG would also be essential, but UNG mutants lacking catalytic activity are viable in all species. In this paper, we present evidence that UNG2 colocalizes with CENP-A and H2AX phosphorylation at centromeres in normally cycling cells. Reduction of UNG2 in human cells blocks CENP-A assembly, and results in reduced cell proliferation, associated with increased frequencies of mitotic abnormalities and rapid cell death. Overexpression of UNG2 induces high levels of CENP-A assembly in human cells. Using a multiphoton laser approach, we demonstrate that UNG2 is rapidly recruited to sites of DNA damage. Taken together, our data are consistent with a model in which the N-terminus of UNG2 interacts with the active site of the enzyme and with chromatin.
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