Title | The expanding landscape of 'oncohistone' mutations in human cancers. |
Publication Type | Journal Article |
Year of Publication | 2019 |
Authors | Nacev, BA, Feng, L, Bagert, JD, Lemiesz, AE, Gao, JJ, Soshnev, AA, Kundra, R, Schultz, N, Muir, TW, C Allis, D |
Journal | Nature |
Volume | 567 |
Issue | 7749 |
Pagination | 473-478 |
Date Published | 2019 Mar |
ISSN | 1476-4687 |
Keywords | Cell Transformation, Neoplastic, Histones, Humans, Lysine, Methylation, Mutation, Neoplasms, Nucleosomes, Protein Domains, Protein Processing, Post-Translational |
Abstract | <p>Mutations in epigenetic pathways are common oncogenic drivers. Histones, the fundamental substrates for chromatin-modifying and remodelling enzymes, are mutated in tumours including gliomas, sarcomas, head and neck cancers, and carcinosarcomas. Classical 'oncohistone' mutations occur in the N-terminal tail of histone H3 and affect the function of polycomb repressor complexes 1 and 2 (PRC1 and PRC2). However, the prevalence and function of histone mutations in other tumour contexts is unknown. Here we show that somatic histone mutations occur in approximately 4% (at a conservative estimate) of diverse tumour types and in crucial regions of histone proteins. Mutations occur in all four core histones, in both the N-terminal tails and globular histone fold domains, and at or near residues that contain important post-translational modifications. Many globular domain mutations are homologous to yeast mutants that abrogate the need for SWI/SNF function, occur in the key regulatory 'acidic patch' of histones H2A and H2B, or are predicted to disrupt the H2B-H4 interface. The histone mutation dataset and the hypotheses presented here on the effect of the mutations on important chromatin functions should serve as a resource and starting point for the chromatin and cancer biology fields in exploring an expanding role of histone mutations in cancer.</p> |
DOI | 10.1038/s41586-019-1038-1 |
Alternate Journal | Nature |
PubMed ID | 30894748 |
PubMed Central ID | PMC6512987 |
Grant List | T32 CA009512 / CA / NCI NIH HHS / United States U24 CA220457 / CA / NCI NIH HHS / United States P01 CA196539 / CA / NCI NIH HHS / United States P41 RR000862 / RR / NCRR NIH HHS / United States P30 CA008748 / CA / NCI NIH HHS / United States F32 GM123659 / GM / NIGMS NIH HHS / United States |