Histone Variants: Guardians of Genome Integrity

Abstract

Chromatin integrity is key for cell homeostasis and for preventing pathological development. Alterations in core chromatin components, histone proteins, recently came into the spotlight through the discovery of their driving role in cancer. Building on these findings, in this review, we discuss how histone variants and their associated chaperones safeguard genome stability and protect against tumorigenesis. Accumulating evidence supports the contribution of histone variants and their chaperones to the maintenance of chromosomal integrity and to various steps of the DNA damage response, including damaged chromatin dynamics, DNA damage repair, and damage-dependent transcription regulation. We present our current knowledge on these topics and review recent advances in deciphering how alterations in histone variant sequence, expression, and deposition into chromatin fuel oncogenic transformation by impacting cell proliferation and cell fate transitions. We also highlight open questions and upcoming challenges in this rapidly growing field.

Keywords: DNA damage response; DNA repair; cancer; cell fate; chromatin; chromosome integrity; genome stability; histone chaperones; histone variants; oncohistones.

Figure 1

Hallmarks of histone variant contributions to the maintenance of genome integrity and cell identity. Diagram depicting the roles of histone variants in the maintenance of chromosome integrity (blue), the DNA damage response (green), and cell fate transitions (yellow). In each case, key features impacted by histone variants are highlighted in red. EMT: epithelial–mesenchymal transition.

Figure 2

Histone variant roles in damaged chromatin accessibility and restoration. Following DNA damage (yellow star), chromatin accessibility is increased through transient decompaction. The deposition and eviction of specific histone variants in the damaged area positively (green arrows) or negatively (red arrows) contribute to chromatin accessibility. The subsequent restoration of chromatin architecture entails the de novo deposition of histone variants (grey arrows). When known, histone chaperones and remodelers involved in these transactions are indicated. Note that the distinction between histone variant roles in chromatin accessibility and restoration is not that strict: some newly deposited histones also increase chromatin accessibility to repair factors and some histone variants that affect chromatin compaction may persist in chromatin thus contributing to chromatin restoration after damage repair. For simplicity, the responses to different types of DNA lesions are gathered on the same scheme.

Figure 3

Histone variant roles in DNA damage signaling and repair pathway choice. DNA damage signaling is stimulated by the eviction of H1 histone variants and by the phosphorylation of H2A.X. Prior to phosphorylation, H2A.X is deposited de novo in damaged chromatin by the histone chaperone FACT. These alterations in histone variants span megabase chromatin domains around DNA lesions. H3.3 and macroH2A histone variants drive DSB repair pathway choice by promoting the recruitment of specific repair factors. The H2A.Z variant is not included in this scheme because of conflicting results regarding its impact on DSB repair. DDR: DNA damage response; HR: homologous recombination; alt-EJ: alternative end joining; NHEJ: non-homologous end joining.

Figure 4

Histone variant point mutations in cancer. (a) The ten most frequently mutated residues in each histone family are shown as red lollipops using the single-letter aminoacid code (source [6], Catalogue Of Somatic Mutations In Cancer database [114] (http://cancer.sanger.ac.uk/cosmic). The positions refer to the mature proteins, which lack the initial methionine. Colored bars represent the globular domains of histone proteins. (b) Top, The most frequent missense mutations in the H3.3 variant are indicated in red, next to the associated tumor types. Bottom, Proposed oncogenic mechanisms relying on three types of molecular changes induced by H3.3 mutations. Histone post-translational modifications (PTMs) including methylation and acetylation are affected in cis (on the same histone molecule) or in trans (through inhibition of histone modifying enymes (HME)). Gene expression programs are rewired, leading to the repression of genes promoting differentiation or the expression of oncogenes. Pathways of genome integrity maintenance are also impacted, such as mismatch repair, DNA double-strand break (DSB) repair or the response to replication stress.

Figure 5

Hallmarks of histone variant dysregulation in cancer. Cellular processes affected by histone variant dysregulation in cancer (highlighted in red) with examples of the associated altered histone variants. DDR: DNA damage response.

Figure 6

Alterations of histone variants in cancer. Cancer-associated histone variant alterations include, in addition to point mutations (see Figure 4), different types of misexpression (up and down arrows indicate overexpression and downregulation, respectively) and incorporation in chromatin at ectopic loci, mediated by specific histone chaperones.