Noncovalent Interactions with SUMO and Ubiquitin Orchestrate Distinct Functions of the SLX4 Complex in Genome Maintenance

Ouyang, Jie; Garner, Elizabeth; Hallet, Alexander; Nguyen, Hai Dang; Rickman, Kimberly A.; Gill, Grace; Smogorzewska, Agata; Zou, Lee

doi:10.1016/j.molcel.2014.11.015

Cited by 72 publications

(98 citation statements)

References 75 publications

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“…The reduction of CPTinduced ␥H2AX by PIAS3 is reminiscent to the observations in cells depleted of MUS81 or SLX4, which are implicated in the cleavage of CPT-induced aberrant replication structures (28,29). Interestingly, we recently found that the function of SLX4 in processing CPT-induced DNA structures is regulated by its binding to SUMO (29). Together, these findings suggest that PIAS3 contributes to the generation of DSBs in CPT-treated cells, possibly working in concert with the SLX4-MUS81 endonuclease complex.…”

Section: Pias3 Regulates Cpt-induced Dsb Formation But Not Resection-mentioning

confidence: 72%

“…Two SUMO ligases, TOPORS and PIAS1, have been implicated in Top1 SUMOylation (32,33). Furthermore, the efficient formation of CPT-induced DSBs requires the SLX4-MUS81 endonuclease complex, which recognizes SUMO through SLX4 (28,29). It is tempting to speculate that PIAS3 contributes to the SUMOylation of Top1 and/or other replication or repair factors that recruit SLX4, promoting the generation or cleavage of reversed forks.…”

Section: Discussionmentioning

confidence: 99%

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The SUMO (Small Ubiquitin-like Modifier) Ligase PIAS3 Primes ATR for Checkpoint Activation

Zou

2016

Journal of Biological Chemistry

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The maintenance of genomic stability relies on the concerted action of DNA repair and DNA damage signaling pathways. The PIAS (protein inhibitor of activated STAT) family of SUMO (small ubiquitin-like modifier) ligases has been implicated in DNA repair, but whether it plays a role in DNA damage signaling is still unclear. Here, we show that the PIAS3 SUMO ligase is important for activation of the ATR (ataxia telangiectasia and Rad3 related)-regulated DNA damage signaling pathway. PIAS3 is the only member of the PIAS family that is indispensable for ATR activation. In response to different types of DNA damage and replication stress, PIAS3 plays multiple roles in ATR activation. In cells treated with camptothecin (CPT), PIAS3 contributes to formation of DNA double-stranded breaks. In UV (ultraviolet light)-or HU (hydroxyurea)-treated cells, PIAS3 is required for efficient ATR autophosphorylation, one of the earliest events during ATR activation. Although PIAS3 is dispensable for ATRIP (ATR-interacting protein) SUMOylation and the ATR-ATRIP interaction, it is required for maintaining the basal kinase activity of ATR prior to DNA damage. In the absence of PIAS3, ATR fails to display normal kinase activity after DNA damage, which accompanies with reduced phosphorylation of ATR substrates. Together, these results suggest that PIAS3 primes ATR for checkpoint activation by sustaining its basal kinase activity, revealing a new function of the PIAS family in DNA damage signaling.Multiple types of post-translational modifications (PTMs), 2 including protein SUMOylation, are important for regulation of the DNA damage response (DDR) from yeast to human (1, 2). Several SUMO E3 ligases, particularly the members of the PIAS family, are shown to modify DDR proteins. In the budding yeast, the PIAS family member Siz1 SUMOylates PCNA during S phase, promoting the recruitment of Srs2 to replication forks to suppress unwanted recombination (3-6). Siz2, the second PIAS ligase in yeast, SUMOylates a large number of DNA replication and repair proteins in response to DNA damage, which may enhance the efficiency of DNA repair by stabilizing multiple protein interactions in repair complexes (7,8). A recent study showed that Siz2 is recruited to sites of DNA damage through its interaction with RPA, a sensor of single-stranded DNA (ssDNA), explaining the regulation of protein SUMOylation by DNA damage (9). Together these findings in yeast clearly show that the PIAS family SUMO ligases are critical regulators of the DDR.In human cells, four members of the PIAS family SUMO ligases have been identified: PIAS1, PIAS2 (PIASx␣/␤), PIAS3, and PIAS4 (PIASy) (10). Two of these SUMO ligases, PIAS1 and PIAS4, are recruited to sites of DNA damage (11). Both PIAS1 and PIAS4 contribute to the efficient recruitment of 53BP1, BRCA1, and RNF168 (11). A number of DDR proteins, such as 53BP1, BRCA1, MDC1, HERC2, RNF168, FNACI, and FANCD2, are SUMOylated by PIAS1 and/or PIAS4. The SUMOylation of these DDR proteins regulate their functions in several different w...

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Section: Pias3 Regulates Cpt-induced Dsb Formation But Not Resection-mentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

The SUMO (Small Ubiquitin-like Modifier) Ligase PIAS3 Primes ATR for Checkpoint Activation

Zou

2016

Journal of Biological Chemistry

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“…Alternatively, StUbls can attach K63-linked ubiquitin chains as a signal important for the DNA damage response (203). While SUMO chains are required for the recruitment of SIM-containing proteins to DNA lesions (117,203,204), it is currently unclear if such chains are free unanchored or substrate-linked SUMO chains. In S. cerevisiae, SUMO chains are implicated to have important roles for synaptonemal complex formation in meiosis (68,205), in the organization of higher-order chromatin and the transcriptional repression of environmental stress-response genes (206).…”

Section: Sumo Chainsmentioning

confidence: 99%

SUMO conjugation – a mechanistic view

Pichler

Fatouros

Lee

et al. 2017

Biomolecular Concepts

207

209

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Abstract:The regulation of protein fate by modification with the small ubiquitin-related modifier (SUMO) plays an essential and crucial role in most cellular pathways. Sumoylation is highly dynamic due to the opposing activities of SUMO conjugation and SUMO deconjugation. SUMO conjugation is performed by the hierarchical action of E1, E2 and E3 enzymes, while its deconjugation involves SUMO-specific proteases. In this review, we summarize and compare the mechanistic principles of how SUMO gets conjugated to its substrate. We focus on the interplay of the E1, E2 and E3 enzymes and discuss how specificity could be achieved given the limited number of conjugating enzymes and the thousands of substrates.

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“…SLX4 contains SUMO-interacting motifs (SIMs) required for binding sumoylated DNA repair proteins, and SLX4 acts directly or indirectly as a SUMO E3 ligase, and its SUMO-related functions are not required for ICL repair but for a general response to replication stress. Accordingly, mutations of SLX4 SIMs do not produce ICLs hypersensitivity but cause common fragile site instability and increased mitotic catastrophe [52,53]. [65].…”

Section: Fa Genes (Fanca B C D1 D2 E F G I J L N P Q) Fmentioning

confidence: 99%

Fanconi anemia: a model disease for studies on human genetics and advanced therapeutics

Bogliolo

Surrallés

2015

Current Opinion in Genetics & Development

160

161

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Noncovalent Interactions with SUMO and Ubiquitin Orchestrate Distinct Functions of the SLX4 Complex in Genome Maintenance

Cited by 72 publications

References 75 publications

The SUMO (Small Ubiquitin-like Modifier) Ligase PIAS3 Primes ATR for Checkpoint Activation

The SUMO (Small Ubiquitin-like Modifier) Ligase PIAS3 Primes ATR for Checkpoint Activation

SUMO conjugation – a mechanistic view

Fanconi anemia: a model disease for studies on human genetics and advanced therapeutics

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