title: ATM Localization and Heterochromatin Repair Depend on Direct Interaction of the 53BP1-BRCT2 Domain with γH2AX.
abstract: 53BP1 plays multiple roles in mammalian DNA damage repair, mediating pathway choice and facilitating DNA double-strand break repair in heterochromatin. Although it possesses a C-terminal BRCT2 domain, commonly involved in phospho-peptide binding in other proteins, initial recruitment of 53BP1 to sites of DNA damage depends on interaction with histone post-translational modifications--H4K20me2 and H2AK13/K15ub--downstream of the early γH2AX phosphorylation mark of DNA damage. We now show that, contrary to current models, the 53BP1-BRCT2 domain binds γH2AX directly, providing a third post-translational mark regulating 53BP1 function. We find that the interaction of 53BP1 with γH2AX is required for sustaining the 53BP1-dependent focal concentration of activated ATM that facilitates repair of DNA double-strand breaks in heterochromatin in G1.
authors.affiliation: Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RQ, UK.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Baldock
authors.affiliation: Cancer Research UK DNA Repair Enzymes Group, Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RQ, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Day
authors.affiliation: Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RQ, UK.
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Wilkinson
authors.affiliation: Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RQ, UK.
authors.forename: Ross
authors.initials: R
authors.lastname: Cloney
authors.affiliation: Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RQ, UK.
authors.forename: Penelope A
authors.initials: PA
authors.lastname: Jeggo
authors.affiliation: Cancer Research UK DNA Repair Enzymes Group, Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RQ, UK.
authors.forename: Antony W
authors.initials: AW
authors.lastname: Oliver
authors.affiliation: Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RQ, UK. Electronic address: f.z.watts@sussex.ac.uk.
authors.forename: Felicity Z
authors.initials: FZ
authors.lastname: Watts
authors.affiliation: Cancer Research UK DNA Repair Enzymes Group, Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RQ, UK. Electronic address: laurence.pearl@sussex.ac.uk.
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Pearl
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D018360:Crystallography, X-Ray; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D006570:Heterochromatin / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D011499:Protein Processing, Post-Translational; D020836:Protein Structure, Quaternary; D034741:RNA, Small Interfering; D014162:Transfection; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D006570:Heterochromatin; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D000071857:Tumor Suppressor p53-Binding Protein 1; C468783:H2AX protein, human; C498301:TP53BP1 protein, human; C498302:Trp53bp1 protein, mouse; C475961:gamma-H2AX protein, mouse