Table 1. Nonproteolytic ubiquitylation:... | Rockefeller University Press

Table 1.

Nonproteolytic ubiquitylation: Selected substrates of E3 ubiquitin ligases that operate in an unperturbed cell cycle

Phase and substrate	E3 ligase	Chain topology	Evidence	Role of ubiquitylation (or deubiquitylation, if indicated)	Counteracting DUB	Reference
G1
PALB2	CRL3^KEAP1	MultimonoUb?	vv (uPD), int, vt, m	Prevents BRCA1-PALB2-BRCA2 complex assembly, inhibiting homology-directed DNA repair	USP11	Orthwein et al., 2015
S
Histone H2A	RING1A,B	MonoUb	vv (ChIP, IF)	Pericentromeric DNA replication	Multiple; not tested for this function	Bravo et al., 2015; Lim et al., 2016
Histone H2B	BRE1	MonoUb	vv (ChIP), m	Promotes nucleosome reassembly and/or stability	—	Trujillo and Osley, 2012
Histone H3	Rtt101^Mms22 (Sc); CRL4?	MultimonoUb	vv (sIP), vv (Wb, ChIP), int, vt, m	Promote H3 deposition in newly synthesized DNA	—	Han et al., 2013
MCM3	CRL3^KEAP1	MultimonoUb?	vv (sIP), int	Undetermined	—	Mulvaney et al., 2016
MCM7	SCF^Dia2 (Sc), CRL2^LRR1 (Xl)	K48-linked (degradation uncertain)	vv (sIP, uPD), vt	Replication termination: Disassembly of the replicative CMG helicase	—	Maric et al., 2014; Moreno et al., 2014; Dewar et al., 2017
MCM10	? (Sc)	DimonoUb	vv (sIP)	Promote PCNA recruitment for elongation during DNA replication	—	Das-Bradoo et al., 2006
SLBP	CRL4^WDR23	MultimonoUb	vv (K-GG), vt, m, int	Promote histone mRNA expression	—	Brodersen et al., 2016
Spt16	Rtt101 (Sc)	K63-linked chain	vv (sIP, uPD), int, vt	Stabilizes FACT complex at replication origins to promote MCM binding	—	Han et al., 2010
S and G2
Aurora A	CRL3^KLHL18	?	vv (sIP), int, vt	Activation of centrosomal Aurora A to promote mitotic entry	—	Moghe et al., 2012
TOP2A	BRCA1	K63-linked chain?	vv (sIP), int	Increase decatenation activity of topoisomerase IIα	—	Lou et al., 2005
TOP2A	RNF168	K63-linked chain	vv (sIP), int, vt, m	Promote DNA decatenation by increasing topoisomerase IIα chromatin association	USP10	Guturi et al., 2016
Mitosis
Aurora B	CRL3^KLHL21	MonoUb?	int, vt, m	Promote UBASH3B-dependent Aurora B translocation to the spindle midzone in anaphase	—	Maerki et al., 2009; Krupina et al., 2016
Cyclin B1	?	K63-linked chain	vv (sIP), int	Stabilize cyclin B1	—	Zhang et al., 2015
Dishevelled DVL3	?	K63-linked chain	DUB^{^a}: vv (sIP, uIP), m	DUB: Promotes spindle orientation, by promoting correct localization of NuMA/dynein at the cell cortex	CYLD	Yang et al., 2014
NuMA	BRCA1?	K63-linked chain	DUB^{^a}: vv (sIP)	DUB: Promotes spindle assembly by stimulating the incorporation of NuMA into spindle poles	BRISC complex	Yan et al., 2015
PLK1	CRL3^KLHL22	MonoUb?	int, vt, m	Remove PLK1 from the kinetochore upon chromosome bi-orientation	USP16	Beck et al., 2013; Zhuo et al., 2015
Survivin	?	K63-linked chain	DUB^{^a}: vv (sIP)	DUB: Dissociates Survivin and the CPC from centromeres	USP9X	Vong et al., 2005
Late M/early G1
CENP-A (Dm)	CRL3^RDX	?	vv (uIP), vt	Stabilize CENP-A to promote its incorporation into centromeres	—	Bade et al., 2014
CENP-A	CRL4^COPS8, CRL4^RBBP7?	MonoUb	vv (sIP), vt, m	Promote interaction with the HJURP histone chaperone and CENP-A loading at centromeres	—	Mouysset et al., 2015; Niikura et al., 2015

Phase and substrate	E3 ligase	Chain topology	Evidence	Role of ubiquitylation (or deubiquitylation, if indicated)	Counteracting DUB	Reference
G1
PALB2	CRL3^KEAP1	MultimonoUb?	vv (uPD), int, vt, m	Prevents BRCA1-PALB2-BRCA2 complex assembly, inhibiting homology-directed DNA repair	USP11	Orthwein et al., 2015
S
Histone H2A	RING1A,B	MonoUb	vv (ChIP, IF)	Pericentromeric DNA replication	Multiple; not tested for this function	Bravo et al., 2015; Lim et al., 2016
Histone H2B	BRE1	MonoUb	vv (ChIP), m	Promotes nucleosome reassembly and/or stability	—	Trujillo and Osley, 2012
Histone H3	Rtt101^Mms22 (Sc); CRL4?	MultimonoUb	vv (sIP), vv (Wb, ChIP), int, vt, m	Promote H3 deposition in newly synthesized DNA	—	Han et al., 2013
MCM3	CRL3^KEAP1	MultimonoUb?	vv (sIP), int	Undetermined	—	Mulvaney et al., 2016
MCM7	SCF^Dia2 (Sc), CRL2^LRR1 (Xl)	K48-linked (degradation uncertain)	vv (sIP, uPD), vt	Replication termination: Disassembly of the replicative CMG helicase	—	Maric et al., 2014; Moreno et al., 2014; Dewar et al., 2017
MCM10	? (Sc)	DimonoUb	vv (sIP)	Promote PCNA recruitment for elongation during DNA replication	—	Das-Bradoo et al., 2006
SLBP	CRL4^WDR23	MultimonoUb	vv (K-GG), vt, m, int	Promote histone mRNA expression	—	Brodersen et al., 2016
Spt16	Rtt101 (Sc)	K63-linked chain	vv (sIP, uPD), int, vt	Stabilizes FACT complex at replication origins to promote MCM binding	—	Han et al., 2010
S and G2
Aurora A	CRL3^KLHL18	?	vv (sIP), int, vt	Activation of centrosomal Aurora A to promote mitotic entry	—	Moghe et al., 2012
TOP2A	BRCA1	K63-linked chain?	vv (sIP), int	Increase decatenation activity of topoisomerase IIα	—	Lou et al., 2005
TOP2A	RNF168	K63-linked chain	vv (sIP), int, vt, m	Promote DNA decatenation by increasing topoisomerase IIα chromatin association	USP10	Guturi et al., 2016
Mitosis
Aurora B	CRL3^KLHL21	MonoUb?	int, vt, m	Promote UBASH3B-dependent Aurora B translocation to the spindle midzone in anaphase	—	Maerki et al., 2009; Krupina et al., 2016
Cyclin B1	?	K63-linked chain	vv (sIP), int	Stabilize cyclin B1	—	Zhang et al., 2015
Dishevelled DVL3	?	K63-linked chain	DUB^a: vv (sIP, uIP), m	DUB: Promotes spindle orientation, by promoting correct localization of NuMA/dynein at the cell cortex	CYLD	Yang et al., 2014
NuMA	BRCA1?	K63-linked chain	DUB^a: vv (sIP)	DUB: Promotes spindle assembly by stimulating the incorporation of NuMA into spindle poles	BRISC complex	Yan et al., 2015
PLK1	CRL3^KLHL22	MonoUb?	int, vt, m	Remove PLK1 from the kinetochore upon chromosome bi-orientation	USP16	Beck et al., 2013; Zhuo et al., 2015
Survivin	?	K63-linked chain	DUB^a: vv (sIP)	DUB: Dissociates Survivin and the CPC from centromeres	USP9X	Vong et al., 2005
Late M/early G1
CENP-A (Dm)	CRL3^RDX	?	vv (uIP), vt	Stabilize CENP-A to promote its incorporation into centromeres	—	Bade et al., 2014
CENP-A	CRL4^COPS8, CRL4^RBBP7?	MonoUb	vv (sIP), vt, m	Promote interaction with the HJURP histone chaperone and CENP-A loading at centromeres	—	Mouysset et al., 2015; Niikura et al., 2015

Shown substrates are not thought to be targeted for proteasomal degradation. Depicted E3 ligase/substrate pairs refer to human proteins, unless indicated. If known, the type of ubiquitylation topology is indicated. A question mark denotes unknown information or a speculative hypothesis. ChIP, chromatin immunoprecipitation; Dm, Drosophila melanogaster; IF, immunofluorescence; int, E3 ligase interaction with substrate; K-GG, ubiquitin profiling; m, mutagenesis of ubiquitylated sites (lysine to arginine); monoUb, monoubiquitylation; Sc, Saccharomyces cerevisiae; sIP, substrate immunoprecipitation and ubiquitin detection; uPD or uIP, ubiquitin pull-down or immunoprecipitation and substrate detection; vt, in vitro ubiquitylation assays; vv, in vivo (method indicated between parentheses); Wb, Western blot; Xl, Xenopus laevis; —, not described.

Available evidence designates the function of the DUB, not an E3 ligase.

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