Histone variants in environmental-stress-induced DNA damage repair

Abstract

Environmental stress such as genotoxic agents can cause DNA damage either indirectly through the generation of reactive oxygen species or directly by interactions with the DNA molecule. Damage to the genetic material may cause mutations and ultimately cancer. Genotoxic mutation can be prevented either by apoptosis or DNA repair. In response to DNA damage, cells have evolved DNA damage responses (DDR) to detect, signal, and repair DNA lesions. Epigenetic mechanisms play critically important roles in DDR, which requires changes in chromatin structure and dynamics to modulate DNA accessibility. Incorporation of histone variants into chromatin is considered as an epigenetic mechanism. Canonical histones can be replaced with variant histones that change chromatin structure, stability, and dynamics. Recent studies have demonstrated involvement of nearly all histone variants in environmental-stress-induced DNA damage repair through various mechanisms, including affecting nucleosome dynamics, carrying variant-specific modification, promoting transcriptional competence or silencing, mediating rearrangement of chromosomes, attracting specific repair proteins, among others. In this review, we will focus on the role of histone variants in DNA damage repair after exposure to environmental genotoxic agents. Understanding the mechanisms regulating environmental exposure-induced epigenetic changes, including replacement of canonical histones with histone variants, will promote the development of strategies to prevent or reverse these changes.

Ionizing Radiation and Complex DNA Damage: From Prediction to Detection Challenges and Biological Significance

“…Previous evidence suggests that deficiencies in repair enzymes like DNA-PK, APE1, and others significantly elevate the accumulation of clustered DNA lesions and genomic instability as reviewed in [141]. Last but not least, one should not disregard the environmental stress fueling DNA damage in cells and tissues through either direct induction of DNA lesions (radiation, chemicals) and epigenetic changes like DNA methylation of key repair gene promoters negatively impacting repair efficiency [142]. Whilst the delayed or incorrect repair of clustered DNA lesions in human results in the generation of mutations and genetic instability in normal tissue, an “optimistic” idea could be that it could also positively serve to cell killing of tumor cells.…”

Quantitative proteome analysis of Merkel cell carcinoma cell lines using SILAC

“…The role of histone variants in the development of carcinomas has been discussed and described in a number of publications [39–46]. As described in a recent review, canonical histones can be replaced with variant histones after environmental-stress-induced DNA damage repair, which subsequently results in a change in chromatin structure and stability [47]. A well-known environmental-stress factor is UV radiation, which in turn is a recognized risk factor for the development of Merkel cell carcinomas.…”

Therapeutic implications of germline vulnerabilities in DNA repair for precision oncology

“…[191] Currently, it is not known how germline variants in core histone proteins may impact DNA repair and response to DNA damaging therapies. [194]…”