Recurrent mutations in H2B histone as novel oncohistones mutations controlling human "jumping genes"

Transposable elements, genes that can `jump` to various locations within the genome, comprise roughly 50% of the mammalian genome. They play an active role in genetic variation, adaptation, and evolution through the duplication or deletion of genes, or by controlling transcription of genes near their insertion sites. As transposon activity can lead to detrimental genome instability, any somatic cell must cope with their destructive potential by preventing their mobility and limiting their expression by transcriptional silencing. We recently discovered and characterized the function of novel chemical modification (proline 1 α-N-terminal methylation (H2BP1me)) of the human histone H2B and found that this modification suppresses human transposon activity. Accordingly, the H2BP1me modification regulates chromatin function to maintain genomic stability. Recently, we identified a set of H2B mutations at this position (e.g. H2BP1) in several epithelial cancers such as lung, breast, colon and ovarian carcinomas that may interfere with the cell`s ability to restrain its transposons. This eventually leads to higher transposon activity, resulting in increased tumor aggressiveness, and could dramatically reduce patient survival. We characterized this set of recurrent H2B cancer mutations and provide the first groundbreaking evidence for this novel oncogenic mechanism.