BBAP monoubiquitylates histone H4 at lysine 91 and selectively modulates the DNA damage response.
Although the BBAP E3 ligase and its binding partner BAL are overexpressed in chemotherapy-resistant lymphomas, the role of these proteins in DNA damage responses remains undefined. Because BAL proteins modulate promoter-coupled transcription and contain structural motifs associated with chromatin remodeling and DNA repair, we reasoned that the BBAP E3 ligase might target nucleosomal proteins. Herein, we demonstrate that BBAP selectively monoubiquitylates histone H4 lysine 91 and protects cells exposed to DNA-damaging agents. Disruption of BBAP-mediated monoubiquitylation of histone H4K91 is associated with the loss of chromatin-associated H4K20 methylase, mono- and dimethyl H4K20, and a delay in the kinetics of 53BP1 foci formation at sites of DNA damage. Because 53BP1 localizes to DNA damage sites, in part, via an interaction with dimethyl H4K20, these data directly implicate BBAP in the monoubiquitylation and additional posttranslational modification of histone H4 and an associated DNA damage response.
Yan
Qingsheng
Q
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Dutt
Shilpee
S
Xu
Rong
R
Graves
Katherine
K
Juszczynski
Przemyslaw
P
Manis
John P
JP
Shipp
Margaret A
MA
D000107:Acetylation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology*; D004317:Doxorubicin / Q000494:pharmacology; D006367:HeLa Cells; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008239:Lysine / Q000378:metabolism*; D008745:Methylation / Q000187:drug effects; D009707:Nucleosomes / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology
D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D009707:Nucleosomes; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D025801:Ubiquitin; D004317:Doxorubicin; D011495:Histone-Lysine N-Methyltransferase; C470730:KMT5A protein, human; C475669:DTX3L protein, human; D044767:Ubiquitin-Protein Ligases; D008239:Lysine; D006918:Hydroxyurea