Histone Variants: Guardians of Genome Integrity

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.