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Title: Mechanism of DNA Methylation-Directed Histone Methylation by KRYPTONITE

Authors:
; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL)
Sponsoring Org.:
USDOE SC OFFICE OF SCIENCE (SC)
OSTI Identifier:
1162715
Report Number(s):
BNL-106661-2014-JA
Journal ID: ISSN 1097-2765
DOE Contract Number:
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Molecular Cell; Journal Volume: 55; Journal Issue: 3
Country of Publication:
United States
Language:
English

Citation Formats

Du, J., Johnson, L., Groth, M., Feng, S., Hale, C., Li, S., Vashisht, A., Gallego-Bartolome, J., Wohlschlegel, J., and Patel et al. Mechanism of DNA Methylation-Directed Histone Methylation by KRYPTONITE. United States: N. p., 2014. Web. doi:10.1016/j.molcel.2014.06.009.
Du, J., Johnson, L., Groth, M., Feng, S., Hale, C., Li, S., Vashisht, A., Gallego-Bartolome, J., Wohlschlegel, J., & Patel et al. Mechanism of DNA Methylation-Directed Histone Methylation by KRYPTONITE. United States. doi:10.1016/j.molcel.2014.06.009.
Du, J., Johnson, L., Groth, M., Feng, S., Hale, C., Li, S., Vashisht, A., Gallego-Bartolome, J., Wohlschlegel, J., and Patel et al. Fri . "Mechanism of DNA Methylation-Directed Histone Methylation by KRYPTONITE". United States. doi:10.1016/j.molcel.2014.06.009.
@article{osti_1162715,
title = {Mechanism of DNA Methylation-Directed Histone Methylation by KRYPTONITE},
author = {Du, J. and Johnson, L. and Groth, M. and Feng, S. and Hale, C. and Li, S. and Vashisht, A. and Gallego-Bartolome, J. and Wohlschlegel, J. and Patel et al.},
abstractNote = {},
doi = {10.1016/j.molcel.2014.06.009},
journal = {Molecular Cell},
number = 3,
volume = 55,
place = {United States},
year = {Fri Aug 01 00:00:00 EDT 2014},
month = {Fri Aug 01 00:00:00 EDT 2014}
}
  • Histone lysine methylation has been linked to the recruitment of mammalian DNA repair factor 53BP1 and putative fission yeast homolog Crb2 to DNA double-strand breaks (DSBs), but how histone recognition is achieved has not been established. Here we demonstrate that this link occurs through direct binding of 53BP1 and Crb2 to histone H4. Using X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy, we show that, despite low amino acid sequence conservation, both 53BP1 and Crb2 contain tandem tudor domains that interact with histone H4 specifically dimethylated at Lys20 (H4-K20me2). The structure of 53BP1/H4-K20me2 complex uncovers a unique five-residue 53BP1 bindingmore » cage, remarkably conserved in the structure of Crb2, that best accommodates a dimethyllysine but excludes a trimethyllysine, thus explaining the methylation state-specific recognition of H4-K20. This study reveals an evolutionarily conserved molecular mechanism of targeting DNA repair proteins to DSBs by direct recognition of H4-K20me2.« less
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  • In order to identify regulators of nuclear organization, Drosophila mutants in the Su(var)3-9 histone H3K9 methyltransferase, RNAi pathway components, and other regulators of heterochromatin-mediated gene silencing were examined for altered nucleoli and positioning of repeated DNAs. Animals lacking components of the H3K9 methylation and RNAi pathways contained disorganized nucleoli, ribosomal DNA (rDNA) and satellite DNAs. The levels of H3K9 dimethylation (H3K9me2) in chromatin associated with repeated DNAs decreased dramatically in Su(var)3-9 and dcr-2 (dicer-2) mutant tissues compared to wild type. We also observed a substantial increase in extrachromosomal repeated DNAs in mutant tissues. The disorganized nucleolus phenotype depends on themore » presence of Ligase 4 (Lig4), and ecc DNA formation is not induced by removal of cohesin. We conclude that H3K9 methylation of rDNA and satellites, maintained by Su(var)3-9, HP1, and the RNAi pathway, is necessary for the structural stability of repeated DNAs, which is mediated through suppression of non-homologous end joining (NHEJ). These results suggest a mechanism for how local chromatin structure can regulate genome stability, and the organization of chromosomal elements and nuclear organelles.« less
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