BMI1 regulates PRC1 architecture and activity through homo- and hetero-oligomerization

Polycomb repressive complex 1 (PRC1) catalyses monoubiquitination of histone H2A on Lys119, promoting gene silencing. Cells at different developmental stages and in different tissues express different PRC1 isoforms. The topology, subunit composition, structural architecture and molecular mechanism of most of these isoforms are still poorly characterized. Here, we have purified a PRC1 isoform comprising subunits RING1B, PCGF2, CBX2 and PHC2, two stable subcomplexes (RING1B‐PCGF2 and RING1B‐PHC2) and the catalytic subunit RING1B in isolation. By crosslinking mass spectrometry, we identified novel interactions between RING1B and the three non‐catalytic subunits. Biochemical, biophysical, and enzymatic data suggest that CBX2 and PHC2 play a structural role, whereas PCGF2 also modulates catalysis. Our data offer insights into the molecular architecture of PRC1 and its histone ubiquitination activity.

show abstract

“…4). This observation is in agreement with the reported structure of the RAWUL domain of PCGF4 and the partial HD1 domain of DPHC2 [14].…”

Section: The Fcs Zinc Finger Domain Of Dphc2 Interacts With Ring Domasupporting

confidence: 93%

“…We used DSS as a crosslinker agent for lysine residues at a C α ‐C α maximum distance of 27 Å. Our data recapitulate inter‐subunit interactions known from available crystal structures of PRC1 domains . For instance, our data show that RING1B and PCGF2 interact through their RING and RAWUL domains.…”

Section: Resultssupporting

confidence: 69%

Topology and enzymatic properties of a canonical Polycomb repressive complex 1 isoform

2019

View full text Add to dashboard Cite

show abstract

“…CTBP2 is a transcriptional corepressor (Furusawa et al 1999) and is a component of the CtBP/LSD1/CoREST repressor complex (Li et al 2017). Ring finger protein BMI1 is a core component of the polycomb-repressive complex 1 (PRC1) (Gray et al 2016), which plays a role in epigenetic regulation of gene silencing. Histone demethylase KDM2B links PRC1 to CpG islands to repress lineage-specific genes during development (He et al 2013).…”

Section: Bcl6 Is Essential For Positive Regulation Of Mll In Pre-b Cellsmentioning

confidence: 99%

Rationale for targeting BCL6 inMLL-rearranged acute lymphoblastic leukemia

et al. 2019

View full text Add to dashboard Cite

Chromosomal rearrangements of the mixed lineage leukemia (MLL) gene occur in ∼10% of B-cell acute lymphoblastic leukemia (B-ALL) and define a group of patients with dismal outcomes. Immunohistochemical staining of bone marrow biopsies from most of these patients revealed aberrant expression of BCL6, a transcription factor that promotes oncogenic B-cell transformation and drug resistance in B-ALL. Our genetic and ChIP-seq (chromatin immunoprecipitation [ChIP] combined with high-throughput sequencing) analyses showed that MLL-AF4 and MLL-ENL fusions directly bound to the BCL6 promoter and up-regulated BCL6 expression. While oncogenic MLL fusions strongly induced aberrant BCL6 expression in B-ALL cells, germline MLL was required to up-regulate Bcl6 in response to physiological stimuli during normal B-cell development. Inducible expression of Bcl6 increased MLL mRNA levels, which was reversed by genetic deletion and pharmacological inhibition of Bcl6, suggesting a positive feedback loop between MLL and BCL6. Highlighting the central role of BCL6 in MLL-rearranged B-ALL, conditional deletion and pharmacological inhibition of BCL6 compromised leukemogenesis in transplant recipient mice and restored sensitivity to vincristine chemotherapy in MLL-rearranged B-ALL patient samples. Oncogenic MLL fusions strongly induced transcriptional activation of the proapoptotic BH3-only molecule BIM, while BCL6 was required to curb MLL-induced expression of BIM. Notably, peptide (RI-BPI) and small molecule (FX1) BCL6 inhibitors derepressed BIM and synergized with the BH3-mimetic ABT-199 in eradicating MLL-rearranged B-ALL cells. These findings uncover MLL-dependent transcriptional activation of BCL6 as a previously unrecognized requirement of malignant transformation by oncogenic MLL fusions and identified BCL6 as a novel target for the treatment of MLLrearranged B-ALL.

show abstract

“…However, PCGF-4 (also known as BMI-1) and RING1A both do not directly ubiquitinate H2A, as only RING1B directly ubiquitinates H2A. Instead complexes containing BMI-1 and RING1A serve to promote the RING1B E3 ligase activity [92].…”

Section: Polycomb Repressive Complexmentioning

confidence: 99%

Processes that Regulate the Ubiquitination of Chromatin and Chromatin-Associated Proteins

Hare¹,

Parvin²

2019

Ubiquitin Proteasome System - Current Insights Into Mechanism Cellular Regulation and Disease

View full text Add to dashboard Cite

Ubiquitin is a post-translational modification important for many different processes in the cell, including antigen presentation and proteosomal degradation of proteins. It is heavily involved in the regulation of chromatin and the proteins that control chromatin-related processes. In this review, we will focus on ubiquitinbased chromatin regulation involved in four different processes. The first is DNA double strand break (DSB) repair and the role that ubiquitin plays in not just recruiting and stimulating DSB repair, but also the choice of pathway. The second is the PAF1 complex, which is involved in transcriptional elongation and interacts with RNAPII. The third is polycomb repressive complexes, specifically polycomb repressive complex 1, which utilizes ubiquitin to repress constitutively inactive genes. The last role of ubiquitin discussed is ubiquitin as a mitotic bookmark, which serves to provide a record of-active genes as cells transit mitosis. Each of these processes has independent pathways, but each is necessary for proper cellular function and organismal health.

show abstract

BMI1 regulates PRC1 architecture and activity through homo- and hetero-oligomerization

Cited by 56 publications

References 67 publications

Topology and enzymatic properties of a canonical Polycomb repressive complex 1 isoform

Topology and enzymatic properties of a canonical Polycomb repressive complex 1 isoform

Rationale for targeting BCL6 inMLL-rearranged acute lymphoblastic leukemia

Processes that Regulate the Ubiquitination of Chromatin and Chromatin-Associated Proteins

Contact Info

Product

Resources

About