Structural highlights
Disease
PHF23_HUMAN A chromosomal aberration involving PHF23 is found in a patient with acute myeloid leukemia (AML). Translocation t(11;17)(p15;p13) with NUP98.
Function
PHF23_HUMAN Acts as a negative regulator of autophagy, through promoting ubiquitination and degradation of LRSAM1, an E3 ubiquitin ligase that promotes autophagy in response to starvation or infecting bacteria.[1]
Publication Abstract from PubMed
Chromosomal NUP98-PHF23 translocation is associated with an aggressive form of acute myeloid leukemia (AML) and poor survival rate. Here, we report the molecular mechanisms by which NUP98-PHF23 recognizes the histone mark H3K4me3 and is inhibited by small molecule compounds, including disulfiram that directly targets the PHD finger of PHF23 (PHF23PHD). Our data support a critical role for the PHD fingers of NUP98-PHF23, and related NUP98-KDM5A and NUP98-BPTF fusions in driving leukemogenesis, and demonstrate that blocking this interaction in NUP98-PHF23 expressing AML cells leads to cell death through necrotic and late apoptosis pathways. An overlap of NUP98-KDM5A oncoprotein binding sites and H3K4me3-positive loci at the Hoxa/b gene clusters and Meis1 in ChIP-seq, together with NMR analysis of the H3K4me3-binding sites of the PHD fingers from PHF23, KDM5A and BPTF, suggests a common PHD finger-dependent mechanism that promotes leukemogenesis by this type of NUP98 fusions. Our findings highlight the direct correlation between the abilities of NUP98-PHD finger fusion chimeras to associate with H3K4me3-enriched chromatin and leukemic transformation.
Mechanistic insights into chromatin targeting by leukemic NUP98-PHF23 fusion.,Zhang Y, Guo Y, Gough SM, Zhang J, Vann KR, Li K, Cai L, Shi X, Aplan PD, Wang GG, Kutateladze TG Nat Commun. 2020 Jul 3;11(1):3339. doi: 10.1038/s41467-020-17098-4. PMID:32620764[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wang Z, Hu J, Li G, Qu L, He Q, Lou Y, Song Q, Ma D, Chen Y. PHF23 (plant homeodomain finger protein 23) negatively regulates cell autophagy by promoting ubiquitination and degradation of E3 ligase LRSAM1. Autophagy. 2014;10(12):2158-70. PMID:25484098 doi:10.4161/auto.36439
- ↑ Zhang Y, Guo Y, Gough SM, Zhang J, Vann KR, Li K, Cai L, Shi X, Aplan PD, Wang GG, Kutateladze TG. Mechanistic insights into chromatin targeting by leukemic NUP98-PHF23 fusion. Nat Commun. 2020 Jul 3;11(1):3339. PMID:32620764 doi:10.1038/s41467-020-17098-4
