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The Bre1/Rad6 machinery: writing the central histone ubiquitin mark on H2B and beyond

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Abstract

Mono-ubiquitination on H2B (H2Bub1) is an evolutionarily conserved histone post-translational modification implicated in various important physiological processes including DNA replication, transcription activation, and DNA damage repair. The Bre1/Rad6 ubiquitination machinery is currently considered to be the sole writer of H2Bub1, but the mechanistic basis by which it operates is unclear. Recently, the RING-type E3 ligase Bre1 was proposed to associate with the E2 enzyme Rad6 through a novel interaction between Bre1 RBD (Rad6 binding domain) and Rad6; and the RING domain of Bre1 that is responsible for the nucleosomal acidic patch binding also interacts with Rad6 to stimulate its catalytic activity. Recent discoveries have yielded evidence for the phenomenon of liquid-liquid phase separation in the context of H2Bub1, and its regulation by other histone post-translational modifications. This review summarizes current knowledge about Bre1/Rad6-mediated H2B ubiquitination, including the physiological functions and the molecular basis for writing and regulation of this central histone ubiquitin mark. Possible models for the Bre1/Rad6 machinery bound to nucleosomes bearing different modifications in the writing step are also disclosed.

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Abbreviations

RBD:

Rad6-binding domain

NCP:

Nucleosome core particle

PTMs:

Post-translational modifications

Me:

Methylation

Ac:

Acetylation

Ub:

Ubiquitination

E1:

Ubiquitin-activating enzyme

E2:

Ubiquitin-conjugating enzyme

E3:

Ubiquitin-ligating enzyme

DSB:

Double-strand break

Paf1:

Polymerase-associated factor 1

HMD:

Histone modification domain

Cryo-EM:

Cryo-electron microscopy

ARM:

Arginine-rich motif

SCFFbx2 :

Skp1-Cullin1-Fbx2-Roc1

LC-MS/MS:

Liquid chromatography-mass spectrometry

LBD:

Lge1-binding domain

XL-MS:

Chemical cross-linking and mass spectrometry

ChIP:

Chromatin immunoprecipitation assay

IDR:

Intrinsically disordered region

LLPS:

Liquid-liquid phase separation

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Funding

This work was supported in part by the National Natural Science Foundation of China (21977090 and 21708036).

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Correspondence to Jia-Bin Li.

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Responsible Editor: Beth Sullivan

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Deng, ZH., Ai, HS., Lu, CP. et al. The Bre1/Rad6 machinery: writing the central histone ubiquitin mark on H2B and beyond. Chromosome Res 28, 247–258 (2020). https://doi.org/10.1007/s10577-020-09640-3

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  • DOI: https://doi.org/10.1007/s10577-020-09640-3

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