Abstract
Canonical histone H3.1 and variant H3.3 deposit at different sites of the chromatin via distinct histone chaperones. Histone H3.1 relies on chaperone CAF-1 to mediate replication-dependent nucleosome assembly during S-phase, while H3.3 variant is regulated and incorporated into the chromatin in a replication-independent manner through HIRA and DAXX/ATRX. Current literature suggests that dysregulated expression of histone chaperones may be implicated in tumor progression. Notably, ectopic expression of CAF-1 can promote a switch between canonical H3.1 and H3 variants in the chromatin, impair the chromatic state, lead to chromosome instability, and impact gene transcription, potentially contributing to carcinogenesis. This review focuses on the chaperone proteins of H3.1 and H3.3, including structure, regulation, as well as their oncogenic and tumor suppressive functions in tumorigenesis.
Highlights
In eukaryotes, histone proteins wrap around the DNA to form nucleosomes, which are the building blocks of chromatin
The chaperone histone cell cycle regulator (HIRA) promotes H3.3 deposition at transient nucleosome-free regions [13]. This could be a salvage pathway to maintain chromatin integrity when CAF-1 mediated H3.1 deposition is impaired during DNA replication [6]
Histone variant H3.3 was initially thought to be a marker of transcriptional activation [59], it was later discovered to be deposited into heterochromatic regions via ATRX/DAXX, indicating that H3.3 deposition in repetitive regions may contribute to chromatin stability [64]
Summary
Histone proteins wrap around the DNA to form nucleosomes, which are the building blocks of chromatin. The HIRA complex interacts with the singlestranded DNA (ssDNA)-binding protein replication factor A (RPA) to deposit newly synthesized H3.3 at gene transcription regulatory elements [42]. As a histone chaperone that mediates H3.3 gapfilling, knockdown of HIRA suppresses the migration and invasion of human breast cancer cell lines LM2 [30].
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