TY - JOUR
T1 - Dot1 promotes H2B ubiquitination by a methyltransferase-independent mechanism
AU - van Welsem, Tibor
AU - Korthout, Tessy
AU - Ekkebus, Reggy
AU - Morais, Dominique
AU - Molenaar, Thom M.
AU - van Harten, Kirsten
AU - Poramba-Liyanage, Deepani W.
AU - Sun, Su Ming
AU - Lenstra, Tineke L.
AU - Srivas, Rohith
AU - Ideker, Trey
AU - Holstege, Frank C. P.
AU - van Attikum, Haico
AU - el Oualid, Farid
AU - Ovaa, Huib
AU - Stulemeijer, Iris J. E.
AU - Vlaming, Hanneke
AU - van Leeuwen, Fred
PY - 2018
Y1 - 2018
N2 - The histone methyltransferase Dot1 is conserved from yeast to human and methylates lysine 79 of histone H3 (H3K79) on the core of the nucleosome. H3K79 methylation by Dot1 affects gene expression and the response to DNA damage, and is enhanced by monoubiquitination of the C-terminus of histone H2B (H2Bub1). To gain more insight into the functions of Dot1, we generated genetic interaction maps of increased-dosage alleles of DOT1. We identified a functional relationship between increased Dot1 dosage and loss of the DUB module of the SAGA co-activator complex, which deubiquitinates H2Bub1 and thereby negatively regulates H3K79 methylation. Increased Dot1 dosage was found to promote H2Bub1 in a dose-dependent manner and this was exacerbated by the loss of SAGA-DUB activity, which also caused a negative genetic interaction. The stimulatory effect on H2B ubiquitination was mediated by the N-terminus of Dot1, independent of methyltransferase activity. Our findings show that Dot1 and H2Bub1 are subject to bi-directional crosstalk and that Dot1 possesses chromatin regulatory functions that are independent of its methyltransferase activity.
AB - The histone methyltransferase Dot1 is conserved from yeast to human and methylates lysine 79 of histone H3 (H3K79) on the core of the nucleosome. H3K79 methylation by Dot1 affects gene expression and the response to DNA damage, and is enhanced by monoubiquitination of the C-terminus of histone H2B (H2Bub1). To gain more insight into the functions of Dot1, we generated genetic interaction maps of increased-dosage alleles of DOT1. We identified a functional relationship between increased Dot1 dosage and loss of the DUB module of the SAGA co-activator complex, which deubiquitinates H2Bub1 and thereby negatively regulates H3K79 methylation. Increased Dot1 dosage was found to promote H2Bub1 in a dose-dependent manner and this was exacerbated by the loss of SAGA-DUB activity, which also caused a negative genetic interaction. The stimulatory effect on H2B ubiquitination was mediated by the N-terminus of Dot1, independent of methyltransferase activity. Our findings show that Dot1 and H2Bub1 are subject to bi-directional crosstalk and that Dot1 possesses chromatin regulatory functions that are independent of its methyltransferase activity.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85066426496&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30203048
U2 - https://doi.org/10.1093/nar/gky801
DO - https://doi.org/10.1093/nar/gky801
M3 - Article
C2 - 30203048
SN - 0305-1048
VL - 46
SP - 11251
EP - 11261
JO - Nucleic Acids Research
JF - Nucleic Acids Research
IS - 21
ER -