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. 2021 Oct 4;3(4):zcab039. doi: 10.1093/narcan/zcab039

Table 1.

Biochemical functions of PRC subunits

Subunit Constituent motifs and domains (InterPro and CanSAR database) PDB structures (including partial structures) Major biochemical function Additional structural, allosteric or regulatory functions if any known
PRC1
RING1A  RING1B (RING2/RNF2)

  • N-terminal RING-type zinc finger

  • C-terminal RAWUL domain

 RING1B

  • RING1B is the major E3 ubiquitin ligase mediating H2AK119ub1, since RING1B loss has a much larger effect on ubiquitination loss than RING1A (21,46)

  • RING1A stimulates the E3 ligase activity of RING1B containing complexes as seen by in vitro reconstitution and ubiquitination assays (47)

  • RING domain-mediated heterodimerization with PCGF enhances interaction with E2 ubiquitin-conjugating enzyme (48–50)

  • RAWUL domain-mediated interaction with either CBX or RYBP/YAF2 results in different PRC1 assembly (51)

  • RING can dimerize with different PCGF paralogs making a scaffold for distinct PRC1 assembly (52)
PCGF1
PCGF2 (MEL18)
PCGF3
PCGF4 (BMI1)
PCGF5
PCGF6

  • N-terminal RING-type zinc finger

  • C-terminal RAWUL domain (PCGF6 lacks the RAWUL domain)

 PCGF1
PCGF4
PCGF5
PCGF6

  • Forms RING domain-mediated heterodimer with RING1 protein and enhances E3-ligase activity (48,49)

  • PCGF2/4 are present in canonical PRC1 while non-canonical PRC1 can contain PCGF1-6 (7)

  • Structural studies have shown differences in the binding partners of RING1B RAWUL domain and PCGF RAWUL domain (53)
CBX2
CBX4
CBX6
CBX7
CBX8

  • N-terminal Chromodomain

  • AT hook (CBX2) or AT-like hook (CBX4,6,7,8)

  • C-terminal Pc Box (also called CBX family C-terminal motif)

 CBX2
CBX4
CBX6
CBX7
CBX8

  • Chromodomain-mediated binding to H3K27me3 (or in some cases H3K9me3), positioning the trimethyl mark within an aromatic cage (54)

  • Pc box-mediated interaction with RING1 (55)

  • Chromodomain-mediated non-specific binding to nucleic acids in CBX4, 6–8 (56)

  • CBX8 chromodomain simultaneously associates with both DNA and H3K27me3 (57)

  • CBX2 participates in nucleosome binding and phase separation through a serine rich patch (58)

  • CBX4 has an E3 SUMO ligase activity which has been shown to enhance sumoylation of CtBP, DNMT3a, BMI-1 (59–61)

  • CBX paralogs have high sequence similarity in the chromodomain and Pc box, yet displaying low similarity outside these domains indicating roles in paralog-specific functions (54,58,62,63)

  • CBX2, 6 and 8 compact nucleosomal arrays in the absence of PRC1 complex, but CBX7 fails to show such compaction. This compaction (and hence, transcriptional repression) is promoted by a highly basic region absent in CBX7 (36)

  • CBX2 undergoes phosphorylation at Ser42 within the chromodomain which alters its binding specificity from H3K27me3 to H3K9me3 in vitro (64)

  • CBX8 has been implicated in transcriptional activation through interactions with activators like AF9/ENL implying functions outside cPRC1 (62,65–67)
PHC1
PHC2
PHC3

  • FCS-type zinc finger

  • C-terminal Sterile alpha motif (SAM)

 PHC1
PHC3

  • SAM-mediated oligomerization with self or other SAM containing proteins, facilitating large scale compaction by phase separation (42,68,69)

  • Such condensates also display enhanced H2A ubiquitination (68)
SCMH1
SCML1
SCML2
SCML4

  • MBT repeats

  • SLED domain

  • SAM

 SCMH1
SCML2

  • Oligomerization via SAM with other SAM containing proteins (70,71)

  • Associates with PRC1 at sub-stoichiometric levels (72,73)
RYBP YAF2

  • N-terminal zinc finger

  • Yaf2/RYBP C-terminal binding motif

 RYBPYAF2

  • RYBP positively modulates the E3 ligase activity of RING1B by stabilizing RING1B protein levels in some cell types (74). However, in mESCs, depletion of RYBP was observed not to affect RING1B protein level (75)

  • RYPB and YAF2 enhance RING1B-PCGF1 mediated H2A ubiquitination activity in vitro. (75)

  • RYBP/YAF2 binds H2AK119ub1 and promotes propagation and deletion of RYBP/YAF2 reduces H2AK119ub1 levels at Polycomb target sites (76)

  • RING1-RYBP/YAF2 interaction is mutually exclusive with RING1-CBX (7)

  • RYBP/YAF2 containing ncPRC1 exhibits stronger in vitro nucleosome monoubiquitination activity than CBX-containing cPRC1 (77)
KDM2B

  • N-terminal Jumonji (JmjC) domain

  • CXXC-type zinc finger

  • PHD-type zinc finger

  • C-terminal F-box domain

 KDM2B

  • Major subunit for targeting to unmethylated CpG islands (77)

  • JmjC-mediated H3K4 and H3K36 demethylase activity for transcriptional repression (78,79)

  
BCOR
BCORL1

  • Non-ankyrin repeat domain

  • Ankyrin repeats

  • BCOR(L)-PCGF1 binding domain

 BCOR
BCORL1

  • N-terminal mediated interaction with other proteins like CtBP1, HSPD1 and BCL6 (80)

  • C-terminal mediated binding to PCGF1 to form the binding surface for KDM2B incorporation (81)
MAX
MGA

  • bHLH DNA binding domain

 MAX

  • bHLH-mediated binding to E-box sequences recognized by Myc, acting as DNA targeting subunits (82)

  • MAX and MGA form a heterodimer for binding to E-box sites (83)

  • MGA additionally contains a conserved DNA binding T-box or T-domain (83)
E2F6
DP1
DP2

  • N-terminal E2F/DP family winged helix DNA binding domain

  • C-terminal E2F Transcription factor CC-MB domain (E2F6)

  • C-terminal Transcription factor DP domain (DP1, DP2)

 DP1
DP2

  • E2F6 interacts with DP1 or DP2 to bind to E2F recognition sequences, acting as DNA targeting subunits (84)
L3MBTL2

  • N-terminal FCS-type zinc finger

  • MBT repeats

 L3MBTL2

  • MBT repeats bind H3 and H4 mono- and di-methylated tails in vitro (85)

  • The methyl binding function has been shown to be dispensable for repression (85)
AUTS2

  • Shown to be transcriptionally activating at target loci (28)

  • AUTS2 containing ncPRC1.5 has been shown to have reduced H2AK119 ubiquitination activity in vitro and AUTS2-RING1B co-bound genomic targets exhibit lower levels of H2AK119ub1 and H3K27me3 in mouse brain cells (28)
PRC2
EZH1
EZH2

  • N-terminal WD repeat binding domain

  • SANT domain

  • CXC domain

  • C-terminal SET domain

 EZH1
EZH2

  • Catalytic subunit with SET domain-mediated H3K27 methylation activity using S-Adenosyl Methionine (SAM-e) as the methyl group donor (11)

  • H3K27 methylation activity is dependent on incorporation into a complex with EED and SUZ12 (11)

  • SET domain (SAM-e binding site) has been the target of the majority of EZH2 inhibitors

  • Loss-of-function mutations in the EED binding domain or catalytic SET domain can destabilize EZH2 and eliminate H3K27 methylation activity (86)

  • Activating mutations of Y641, A677, A687 in the SET domain enhance H3K27me3 activity (87–90)
EED

  • WD-40 repeats

 EED

  • WD-40 repeats form the aromatic cage that interacts with the histone methylation mark (11)

  • EED binding to histone trimethyl mark allosterically activates EZH2 catalytic activity (34)

  • Mutations in the aromatic cage can completely eliminate recognition of the histone methylation mark (52)
SUZ12

  • C-terminalVEFS Box

 SUZ12

  • Stabilizes PRC2 complex through interactions with EZH and EED (91)
RBBP4/RbAp48
RBBP7/RbAp46

  • WD40 repeats

 RBBP4
RBBP7

  • Involved in histone binding, particularly H4. Found in multiple chromatin binding complexes like CAF-1, HDAC, NuRD, NURF and PRC2 complex (92–94)
PCL1/ PHF1
PCL2/ MTF2
PCL3/ PHF19

  • N-terminal TUDOR domain

  • PHD-type zinc finger

  • C-terminal Polycomb-like MTF2 factor 2 domain

 PCL1
PCL2
PCL3

  • Binds to unmethylated CpG motifs, facilitating PRC2 recruitment to specific loci (24)

  • Tudor domain binds to H3K36me, facilitating PRC2 recruitment and H3K27me3 deposition at those sites (95,96)
AEBP2 Zinc finger AEBP2

  • Boosts the histone methyl transferase (HMTase) activity of PRC2 on ubiquitinated H2A nucleosomes in vitro (97)

  • Recognizes H2AK119ub1 to facilitate PRC2 recruitment (22)

  • Acts as DNA targeting subunit (91,98)

  • Mimics unmethylated H3K4 binding to RBBP4 which allosterically activates PRC2 activity (11)

  • AEBP2-null mESCs have been reported to show increased H3K27me3 levels due to formation of a hybrid PRC2 in these cells consisting of PRC2 core-JARID2-PCL2 (99)

  • Two isoforms identified in human- an adult specific isoform (51 kDa) and an embryo-specific smaller isoform (32 kDa), both containing the zinc fingers (100)
JARID2

  • ARID DNA binding domain

  • Jmj domain

  • Zinc finger

 JARID2

  • Boosts the HMTase activity of PRC2 in vitro (101)

  • Recognizes H2AK119ub1 to facilitate PRC2 recruitment (22)

  • JARID2K116 can be methylated by PRC2 (JARID2K116me3) which can bind to EED and allosterically stimulate PRC2 enzymatic activity (102)
PALI1
PALI2

  • Helix-turn-helix DNA binding domain

 PALI1

  • Vertebrate specific subunits, mutually exclusive in PRC2 with AEBP2 (103)

  • PALI1 facilitate chromatin binding and promotes PRC2 enzymatic activity (104)

  • PRC2 methylates PALI1 at K1241 which allosterically activates PRC2 enzymatic activity through EED (104)
EPOP

  • BC box

  • Recruits Elongin BC to PRC2 sites (105)
EZHIP/CATACOMB

  • Inhibitor of allosterically activated PRC2 H3K27me3 catalytic activity (106–108)