scholarly journals Structural basis for the E3 ligase activity enhancement of yeast Nse2 by SUMO-interacting motifs

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Nathalia Varejão ◽  
Jara Lascorz ◽  
Joan Codina-Fabra ◽  
Gemma Bellí ◽  
Helena Borràs-Gas ◽  
...  
Keyword(s):  
Dna Damage ◽  
E3 Ligase ◽  
Ring Domain ◽  
Structural Basis ◽  
Post Translational Modification ◽  
A Subunit ◽  
Sumo E3 Ligase ◽  
Activity Enhancement ◽  
Chromosome Integrity ◽  
Key Events

AbstractPost-translational modification of proteins by ubiquitin and ubiquitin-like modifiers, such as SUMO, are key events in protein homeostasis or DNA damage response. Smc5/6 is a nuclear multi-subunit complex that participates in the recombinational DNA repair processes and is required in the maintenance of chromosome integrity. Nse2 is a subunit of the Smc5/6 complex that possesses SUMO E3 ligase activity by the presence of a SP-RING domain that activates the E2~SUMO thioester for discharge on the substrate. Here we present the crystal structure of the SUMO E3 ligase Nse2 in complex with an E2-SUMO thioester mimetic. In addition to the interface between the SP-RING domain and the E2, the complex reveals how two SIM (SUMO-Interacting Motif) -like motifs in Nse2 are restructured upon binding the donor and E2-backside SUMO during the E3-dependent discharge reaction. Both SIM interfaces are essential in the activity of Nse2 and are required to cope with DNA damage.

scholarly journals SUMO E3 ligase Mms21 prevents spontaneous DNA damage induced genome rearrangements

2017 ◽  
Author(s):  
Jason Liang ◽  
Bin-zhong Li ◽  
Alexander P. Tan ◽  
Richard D. Kolodner ◽  
Christopher D. Putnam ◽  
...  
Keyword(s):  
Dna Damage ◽  
E3 Ligase ◽  
Genome Rearrangements ◽  
Dna Helicase ◽  
Dna Lesions ◽  
Genome Maintenance ◽  
New Paradigm ◽  
A Subunit ◽  
Sumo E3 Ligase ◽  
Break Induced Replication

AbstractMms21, a subunit of the Smc5/6 complex, possesses an E3 ligase activity for the Small Ubiquitin-like MOdifier (SUMO), which has a major, but poorly understood role in genome maintenance. Here we show mutations that inactivate the E3 ligase activity of Mms21 cause Rad52- and Pol32-dependent break-induced replication (BIR), which specifically requires the Rrm3 DNA helicase. Interestingly, mutations affecting both Mms21 and the Sgs1 helicase, but not sumoylation of Sgs1, cause further accumulation of genome rearrangements, indicating the distinct roles of Mms21 and Sgs1 in suppressing genome rearrangements. Whole genome sequencing further revealed that the Mre11 endonuclease prevents microhomology-mediated translocations and hairpin-mediated inverted duplications in the mms21 mutant. Consistent with the accumulation of endogenous DNA lesions, mms21 cells accumulate spontaneous Ddc2 foci and display a hyper-activated DNA damage checkpoint. Together, these findings support a new paradigm that Mms21 prevents the accumulation of spontaneous DNA lesions that cause diverse genome rearrangements.

scholarly journals Structural basis for DNA damage-induced phosphoregulation of MDM2 RING domain

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Helge M. Magnussen ◽  
Syed F. Ahmed ◽  
Gary. J. Sibbet ◽  
Ventzislava A. Hristova ◽  
Koji Nomura ◽  
...  
Keyword(s):  
Dna Damage ◽  
Ring Domain ◽  
Structural Basis

scholarly journals Structural basis for catalytic activation by the human ZNF451 SUMO E3 ligase

2015 ◽  
Vol 22 (12) ◽  
pp. 968-975 ◽  
Author(s):  
Laurent Cappadocia ◽  
Andrea Pichler ◽  
Christopher D Lima
Keyword(s):  
E3 Ligase ◽  
Structural Basis ◽  
Catalytic Activation ◽  
Sumo E3 Ligase

scholarly journals SUMO E3 ligase Mms21 prevents spontaneous DNA damage induced genome rearrangements

PLoS Genetics ◽  
2018 ◽  
Vol 14 (3) ◽  
pp. e1007250 ◽  
Author(s):  
Jason Liang ◽  
Bin-zhong Li ◽  
Alexander P. Tan ◽  
Richard D. Kolodner ◽  
Christopher D. Putnam ◽  
...  
Keyword(s):  
Dna Damage ◽  
E3 Ligase ◽  
Genome Rearrangements ◽  
Sumo E3 Ligase

SUMO E3-Ligase Regulates DNA Damage-Dependent Exchange of the Histone Variant H2A.Z-2

2013 ◽  
Vol 87 (2) ◽  
pp. S22
Author(s):  
I. Nishibuchi ◽  
S. Tashiro ◽  
H. Suzuki ◽  
A. Kinomura ◽  
J. Sun ◽  
...  
Keyword(s):  
Dna Damage ◽  
E3 Ligase ◽  
Histone Variant ◽  
Sumo E3 Ligase

scholarly journals Regulation of DNA Replication Licensing and Re-Replication by Cdt1

2021 ◽  
Vol 22 (10) ◽  
pp. 5195
Author(s):  
Hui Zhang
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Replication ◽  
Genome Stability ◽  
E3 Ligase ◽  
S Phase ◽  
Replication Initiation ◽  
Nuclear Antigen ◽  
Repair Synthesis ◽  
Ubiquitin E3 Ligase

In eukaryotic cells, DNA replication licensing is precisely regulated to ensure that the initiation of genomic DNA replication in S phase occurs once and only once for each mitotic cell division. A key regulatory mechanism by which DNA re-replication is suppressed is the S phase-dependent proteolysis of Cdt1, an essential replication protein for licensing DNA replication origins by loading the Mcm2-7 replication helicase for DNA duplication in S phase. Cdt1 degradation is mediated by CRL4Cdt2 ubiquitin E3 ligase, which further requires Cdt1 binding to proliferating cell nuclear antigen (PCNA) through a PIP box domain in Cdt1 during DNA synthesis. Recent studies found that Cdt2, the specific subunit of CRL4Cdt2 ubiquitin E3 ligase that targets Cdt1 for degradation, also contains an evolutionarily conserved PIP box-like domain that mediates the interaction with PCNA. These findings suggest that the initiation and elongation of DNA replication or DNA damage-induced repair synthesis provide a novel mechanism by which Cdt1 and CRL4Cdt2 are both recruited onto the trimeric PCNA clamp encircling the replicating DNA strands to promote the interaction between Cdt1 and CRL4Cdt2. The proximity of PCNA-bound Cdt1 to CRL4Cdt2 facilitates the destruction of Cdt1 in response to DNA damage or after DNA replication initiation to prevent DNA re-replication in the cell cycle. CRL4Cdt2 ubiquitin E3 ligase may also regulate the degradation of other PIP box-containing proteins, such as CDK inhibitor p21 and histone methylase Set8, to regulate DNA replication licensing, cell cycle progression, DNA repair, and genome stability by directly interacting with PCNA during DNA replication and repair synthesis.

scholarly journals Targeting Hedgehog Signalling through the Ubiquitylation Process: The Multiple Roles of the HECT-E3 Ligase Itch

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 98 ◽  
Author(s):  
Paola Infante ◽  
Ludovica Lospinoso Severini ◽  
Flavia Bernardi ◽  
Francesca Bufalieri ◽  
Lucia Di Marcotullio
Keyword(s):  
E3 Ligase ◽  
Multiple Roles ◽  
Post Translational Modification ◽  
Therapeutic Approaches ◽  
Cellular Functions ◽  
Hedgehog Signalling ◽  
Promising Target ◽  
Important Pathway ◽  
Multiple Levels

Hedgehog signalling (Hh) is a developmental conserved pathway strongly involved in cancers when deregulated. This important pathway is orchestrated by numerous regulators, transduces through distinct routes and is finely tuned at multiple levels. In this regard, ubiquitylation processes stand as essential for controlling Hh pathway output. Although this post-translational modification governs proteins turnover, it is also implicated in non-proteolytic events, thereby regulating the most important cellular functions. The HECT E3 ligase Itch, well known to control immune response, is emerging to have a pivotal role in tumorigenesis. By illustrating Itch specificities on Hh signalling key components, here we review the role of this HECT E3 ubiquitin ligase in suppressing Hh-dependent tumours and explore its potential as promising target for innovative therapeutic approaches.

scholarly journals Human papillomavirus E7 oncoprotein targets RNF168 to hijack the host DNA damage response

2019 ◽  
Vol 116 (39) ◽  
pp. 19552-19562 ◽  
Author(s):  
Justine Sitz ◽  
Sophie Anne Blanchet ◽  
Steven F. Gameiro ◽  
Elise Biquand ◽  
Tia M. Morgan ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Dna Damage ◽  
Cancer Cells ◽  
Genomic Instability ◽  
E3 Ligase ◽  
Human Papillomaviruses ◽  
Double Strand Breaks ◽  
Nuclear Bodies ◽  
Dna Double Strand Breaks ◽  
Strand Breaks

High-risk human papillomaviruses (HR-HPVs) promote cervical cancer as well as a subset of anogenital and head and neck cancers. Due to their limited coding capacity, HPVs hijack the host cell’s DNA replication and repair machineries to replicate their own genomes. How this host–pathogen interaction contributes to genomic instability is unknown. Here, we report that HPV-infected cancer cells express high levels of RNF168, an E3 ubiquitin ligase that is critical for proper DNA repair following DNA double-strand breaks, and accumulate high numbers of 53BP1 nuclear bodies, a marker of genomic instability induced by replication stress. We describe a mechanism by which HPV E7 subverts the function of RNF168 at DNA double-strand breaks, providing a rationale for increased homology-directed recombination in E6/E7-expressing cervical cancer cells. By targeting a new regulatory domain of RNF168, E7 binds directly to the E3 ligase without affecting its enzymatic activity. As RNF168 knockdown impairs viral genome amplification in differentiated keratinocytes, we propose that E7 hijacks the E3 ligase to promote the viral replicative cycle. This study reveals a mechanism by which tumor viruses reshape the cellular response to DNA damage by manipulating RNF168-dependent ubiquitin signaling. Importantly, our findings reveal a pathway by which HPV may promote the genomic instability that drives oncogenesis.

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