HBO1, a MYSTerious KAT and its links to cancer

Abstract

The histone acetyltransferase HBO1, also known as KAT7, is a major chromatin modifying enzyme responsible for H3 and H4 acetylation. It is found within two distinct tetrameric complexes, the JADE subunit-containing complex and BRPF subunit-containing complex. The HBO1-JADE complex acetylates lysine 5, 8 and 12 of histone H4, and the HBO1-BRPF complex acetylates lysine 14 of histone H3. HBO1 regulates gene transcription, DNA replication, DNA damage repair, and centromere function. It is involved in diverse signaling pathways and plays crucial roles in development and stem cell biology. Recent work has established a strong relationship of HBO1 with the histone methyltransferase MLL/KMT2A in acute myeloid leukemia. Here, we discuss functional and pathological links of HBO1 to cancer, highlighting the underlying mechanisms that may pave the way to the development of novel anti-cancer therapies.

Keywords: Acetylation; Acetyltransferase; Cancer; HBO1; KAT; Transcription.

Figure 1.. Human HBO1 complexes: alternate subunit assemblies, protein domains and histone acetylation specificities.

a) Subunit interactions and protein domains within the two types of HBO1 tetrameric complexes. A dotted line indicates physical interaction between subunits or between reader modules and chromatin marks. The PZP domain in BRPF2/3 also binds unmethylated H3K4 and DNA, like the one in JADE proteins. BRPF2/3 also contain a bromodomain (before the PWWP domain) that can bind acetylated H3 or H4. b) HBO1 histone tail acetylation specificity is switched by complex components. JADE1/2/3-containing HBO1 complexes acetylate histone H4 on lysines 5, 8 and 12, while BRPF2/3-containing HBO1 complexes acetylate histone H3 lysine 14. c) Substrate specificity regulated by the chromatin context. JADE-containing HBO1 complexes also acetylate histone H3 when the nucleosome is symmetrically tri-methylated on H3K4.

Figure 2.. Cooperative binding to chromatin by HBO1 and MLL complexes.

1-HBO1 can associate with chromatin at specific loci, possibly through pre-existing H3K4 methylated sites, and recruits the MLL complex through physical interaction to proximal unmethylated CpGs. 2-The MLL complex bound to unmethylated CpGs deposits tri-methylated H3K4 marks and recruits the HBO1 complex through physical interaction and/or H3K4me3 recognition by the ING4/5 subunit.

Figure 3.. Aberrant transcriptional activation by leukemic fusion proteins of MLL and HBO1 complexes.

a) Structures of MLL and MLL fusion proteins. The HBO1 complex binds to the THD2 domain of MLL and MLL fusions. b) Models of transcriptional activation by MLL-ELL and NUP98-HBO1. MLL-ELL associates with a HBO1 complex and an AEP coactivator complex to activate transcription. NUP98-HBO1 associates with MLL and activate transcription via its NUP98 portion. c) Structures of NUP98 fusion proteins found in leukemia patients.