Genome protection: histone H4 and beyond

Abstract

Histone proteins regulate cellular factors’ accessibility to DNA, and histone dosage has previously been linked with DNA damage susceptibility and efficiency of DNA repair pathways. Surplus histones are known to impede the DNA repair process by interfering with the homologous recombination-mediated DNA repair in Saccharomyces cerevisiae. Here, we discuss the recent finding of association of methyl methanesulfonate (MMS) resistance with the reduced histone H4 gene dosage in the pathogenic yeast Candida glabrata. We have earlier shown that while the low histone H3 gene dosage led to MMS susceptibility, the lack of two H4-encoding ORFs, CgHHF1 and CgHHF2, led to resistance to MMS-induced DNA damage. This resistance was linked with a higher rate of homologous recombination (HR). Taking these findings further, we review the interactome analysis of histones H3 and H4 in C. glabrata. We also report that the arginine residue present at the 95th position in the C-terminal tail of histone H4 protein is required for complementation of the MMS resistance in the Cghhf1Δhhf2Δ mutant, thereby pointing out a probable role of this residue in association with HR factors. Additionally, we present evidence that reduction in H4 protein levels may constitute an important part of varied stress responses in C. glabrata. Altogether, we present an overview of histone H4 dosage, HR-mediated repair of damaged DNA and stress resistance in this opportunistic human fungal pathogen.

Inhibition of the Growth of Breast Cancer-Associated Brain Tumors by the Osteocyte-Derived Conditioned Medium

“…While the action of histone H4 was hypothesized as a potential inducer of apoptosis, its extensive regulatory effects on CXCL1 and CXCL5, as well as the other tumor suppressors such as LIMA1, DSP, p53, and Trail in osteocyte-derived CM, were unexpected ( Figure 7 J). Histone H4 is one of the most highly conserved proteins, critically important for the structural integrity and accessibility of chromatin, and it is mostly located inside the nucleus to form octameric nucleosomes [ 32 ]. Interestingly, extracellular histone H4, which is a byproduct of cell death, is reported to serve as a warning signal and contribute to activating innate immune responses [ 43 ].…”

“…We also conducted whole-genome proteomics and predicted tumor-suppressing protein candidates that were enriched in CM. One candidate, identified by mass spectrometry, was histone H4, one of the core histones to form octameric nucleosomes [ 32 ]. Histone H4 is reported to increase caspase 3 activity and induce apoptosis in neutrophils [ 33 , 34 ].…”

FnCas12a/crRNA-Mediated Genome Editing in Eimeria tenella

“…Because Histone H4 is one of the five major histone proteins involved in the structure of chromatin in eukaryotic cells, which is a core component of the nucleosome and plays a vital role in DNA repair, DNA replication, transcription regulation, and chromosomal stability ( Grover et al, 2018 ; Kumar et al, 2020 ), we selected EtHistone H4 as the target gene. The fragment of EtHistone H4 harboring the target sites for cleavage was amplified and then inserted into the pJET1.2 vector.…”

An epigenetically inherited UV hyper-resistance phenotype in Saccharomyces cerevisiae

“…These connections suggest that histone dosage may play a role in the UVHR response. Prior studies have implicated changes in histone dosage in the response to DNA damage [27][28][29], and thus additional studies are merited to further explore this potential mechanism.…”