Methyllysine reader plant homeodomain (PHD) finger protein 20-like 1 (PHF20L1) antagonizes DNA (cytosine-5) methyltransferase 1 (DNMT1) proteasomal degradation.
Inheritance of DNA cytosine methylation pattern during successive cell division is mediated by maintenance DNA (cytosine-5) methyltransferase 1 (DNMT1). Lysine 142 of DNMT1 is methylated by the SET domain containing lysine methyltransferase 7 (SET7), leading to its degradation by proteasome. Here we show that PHD finger protein 20-like 1 (PHF20L1) regulates DNMT1 turnover in mammalian cells. Malignant brain tumor (MBT) domain of PHF20L1 binds to monomethylated lysine 142 on DNMT1 (DNMT1K142me1) and colocalizes at the perinucleolar space in a SET7-dependent manner. PHF20L1 knockdown by siRNA resulted in decreased amounts of DNMT1 on chromatin. Ubiquitination of DNMT1K142me1 was abolished by overexpression of PHF20L1, suggesting that its binding may block proteasomal degradation of DNMT1K142me1. Conversely, siRNA-mediated knockdown of PHF20L1 or incubation of a small molecule MBT domain binding inhibitor in cultured cells accelerated the proteasomal degradation of DNMT1. These results demonstrate that the MBT domain of PHF20L1 reads and controls enzyme levels of methylated DNMT1 in cells, thus representing a novel antagonist of DNMT1 degradation.
From New England Biolabs Inc., Ipswich, Massachusetts 01938 and.
Pierre-Olivier
PO
Estève
Jolyon
J
Terragni
Kanneganti
K
Deepti
Hang Gyeong
HG
Chin
Nan
N
Dai
Alexsandra
A
Espejo
Ivan R
IR
Corrêa
Mark T
MT
Bedford
Sriharsa
S
Pradhan
D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives*; D060066:Protein Interaction Maps; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D034622:RNA Interference; D015854:Up-Regulation
D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; C000588559:PHF20L1 protein, human; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; D008239:Lysine
DNA Methylation; DNA Methyltransferase; DNA-binding Protein; MBT Domain; PHF20L1; Protein Degradation; Protein Methylation; SET7; UNC1215