2LVM

Solution structure of human 53BP1 tandem Tudor domains in complex with a histone H4K20me2 peptide

Summary for 2LVM

• Entry DOI: 10.2210/pdb2lvm/pdb
• NMR Information: BMRB: 18579
• Descriptor: Tumor suppressor p53-binding protein 1, Histone H4 (2 entities in total)
• Functional Keywords: dimethylation, cell cycle
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: Q12888 P62805
• Total number of polymer chains: 2
• Total formula weight: 15668.82

Authors

Cui, G.,Botuyan, M.,Mer, G. (deposition date: 2012-07-07, release date: 2012-12-12, Last modification date: 2013-04-03)

Primary citation

Tang, J.,Cho, N.W.,Cui, G.,Manion, E.M.,Shanbhag, N.M.,Botuyan, M.V.,Mer, G.,Greenberg, R.A.
Acetylation limits 53BP1 association with damaged chromatin to promote homologous recombination.
Nat.Struct.Mol.Biol., 20:317-325, 2013

PubMed Abstract: The pathogenic sequelae of BRCA1 mutation in human and mouse cells are mitigated by concomitant deletion of 53BP1, which binds histone H4 dimethylated at Lys20 (H4K20me2) to promote nonhomologous end joining, suggesting that a balance between BRCA1 and 53BP1 regulates DNA double strand-break (DSB) repair mechanism choice. Here we document that acetylation is a key determinant of this balance. TIP60 acetyltransferase deficiency reduced BRCA1 at DSB chromatin with commensurate increases in 53BP1, whereas HDAC inhibition yielded the opposite effect. TIP60-dependent H4 acetylation diminished 53BP1 binding to H4K20me2 in part through disruption of a salt bridge between H4K16 and Glu1551 in the 53BP1 Tudor domain. Moreover, TIP60 deficiency impaired homologous recombination and conferred sensitivity to PARP inhibition in a 53BP1-dependent manner. These findings demonstrate that acetylation in cis to H4K20me2 regulates relative BRCA1 and 53BP1 DSB chromatin occupancy to direct DNA repair mechanism.

PubMed: 23377543
DOI: 10.1038/nsmb.2499

Experimental method

SOLUTION NMR