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MST2 kinase suppresses rDNA transcription in response to DNA damage by phosphorylating nucleolar histone H2B
Author(s) -
Pefani Dafni Eleftheria,
Tognoli Maria Laura,
Pirincci Ercan Deniz,
Gorgoulis Vassilis,
O'Neill Eric
Publication year - 2018
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201798760
Subject(s) - radiation oncology , library science , medicine , oncology , radiation therapy , computer science
The heavily transcribed rDNA repeats that give rise to the ribosomal RNA are clustered in a unique chromatin structure, the nucleolus. Due to its highly repetitive nature and transcriptional activity, the nucleolus is considered a hotspot of genomic instability. Breaks in rDNA induce a transient transcriptional shut down to conserve energy and promote rDNA repair; however, how nucleolar chromatin is modified and impacts on rDNA repair is unknown. Here, we uncover that phosphorylation of serine 14 on histone H2B marks transcriptionally inactive nucleolar chromatin in response to DNA damage. We identified that the MST 2 kinase localises at the nucleoli and targets phosphorylation of H2BS14p in an ATM ‐dependent manner. We show that establishment of H2 BS 14p is necessary for damage‐induced rDNA transcriptional shut down and maintenance of genomic integrity. Ablation of MST 2 kinase, or upstream activators, results in defective establishment of nucleolar H2 BS 14p, perturbed DNA damage repair, sensitisation to rDNA damage and increased cell lethality. We highlight the impact of chromatin regulation in the rDNA damage response and targeting of the nucleolus as an emerging cancer therapeutic approach.