Histone H3.3 and cancer: A potential reader connection

Abstract

The building block of chromatin is nucleosome, which consists of 146 base pairs of DNA wrapped around a histone octamer composed of two copies of histone H2A, H2B, H3, and H4. Significantly, the somatic missense mutations of the histone H3 variant, H3.3, are associated with childhood and young-adult tumors, such as pediatric high-grade astrocytomas, as well as chondroblastoma and giantcell tumors of the bone. The mechanisms by which these histone mutations cause cancer are by and large unclear. Interestingly, two recent studies identified BS69/ZMYND11, which was proposed to be a candidate tumor suppressor, as a specific reader for a modified form of H3.3 (H3.3K36me3). Importantly, some H3.3 cancer mutations are predicted to abrogate the H3.3K36me3/BS69 interaction, suggesting that this interaction may play an important role in tumor suppression. These new findings also raise the question of whether H3.3 cancer mutations may lead to the disruption and/or gain of interactions of additional cellular factors that contribute to tumorigenesis.histone | H3.3 | H3.3K36me3 | cancer | BS69

Suppression of Enhancer Overactivation by a RACK7-Histone Demethylase Complex

“…Although the enzymology of KDM5C as a histone H3K4me3 demethylase is well understood (Lan et al, 2008; Lan and Shi, 2015; Mosammaparast and Shi, 2010), an important question that remains unanswered is how it is recruited to its target regions. We next asked whether RACK7 might play a recruiting role for KDM5C to chromatin.…”

“…For instance, enzymes that are involved in modifying the chromatin landscapes of enhancers, such as the histone methyltransferases MLL2, MLL3, MLL4, the H3K4me2/3-specific demethylase KDM5C, the acetyltransferases CBP/p300, as well as the histone H3 variant, H3.3, have been found to be frequently mutated in various cancers (Blair et al, 2011; Ford and Dingwall, 2015; Lan and Shi, 2015; Rasmussen and Staller, 2014; Wang et al, 2013). Consistently, recent cancer genome sequence efforts have also identified genetic mutations of enhancers and super-enhancers, which regulate the expression of oncogenes and tumor suppressors (Fredriksson et al, 2014; Melton et al, 2015).…”

The effects of chromatin organization on variation in mutation rates in the genome

“…Chromatin modifiers are frequently mutated in medulloblastomas 71 and in small cell lung cancer 72 . Similarly, pediatric glioblastomas 73 and some other brain tumors (e.g., diffuse intrinsic pontine glioma and high-grade astrocytoma) are characterized by recurrent driver mutations in H3F3A encoding replication-independent histone variant H3.3 (reviewed in 74 ). The same gene is mutated in chondroblastoma, chondrosarcoma, and osteosarcoma 74 .…”

“…Similarly, pediatric glioblastomas 73 and some other brain tumors (e.g., diffuse intrinsic pontine glioma and high-grade astrocytoma) are characterized by recurrent driver mutations in H3F3A encoding replication-independent histone variant H3.3 (reviewed in 74 ). The same gene is mutated in chondroblastoma, chondrosarcoma, and osteosarcoma 74 . It has been shown that mutations in H3.3 may alter either local or global histone methylation patterns (reviewed in 74 ).…”

“…The same gene is mutated in chondroblastoma, chondrosarcoma, and osteosarcoma 74 . It has been shown that mutations in H3.3 may alter either local or global histone methylation patterns (reviewed in 74 ). Furthermore, some cancers are characterized by recurrent mutations in genes encoding de novo DNA methyltransferases, DNMT3A and DNMT3B.…”