Sumoylation of the Rad1 nuclease promotes DNA repair and regulates its DNA association

Sarangi, Prabha; Bartošová, Zdeňka; Altmannová, Veronika; Holland, Cory; Chavdarova, Melita; Lee, Sang Eun; Krejčí, Lumír; Zhao, Xiaolan

doi:10.1093/nar/gku300

Cited by 25 publications

(33 citation statements)

References 80 publications

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“…Whether SLX4 defines a novel class of SUMO E3 ligases structured around the BTB domain awaits the identification of additional BTB proteins with SUMO-E3 ligase activity. Interestingly, as we were finalizing our study, Slx4 was reported to be necessary in S. cerevisiae for SUMOylation of Rad1 XPF by Siz1 and Siz2 SUMO E3 ligases (Sarangi et al, 2014). Our results show that evolution has provided the human protein with the ability to directly SUMOylate XPF and that this relies on the acquisition of the BTB domain absent in the yeast protein.…”

Section: Slx4 a New Type Of Sumo E3 Ligase?supporting

confidence: 53%

The SLX4 Complex Is a SUMO E3 Ligase that Impacts on Replication Stress Outcome and Genome Stability

et al. 2015

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The SLX4 Fanconi anemia protein is a tumor suppressor that may act as a key regulator that engages the cell into specific genome maintenance pathways. Here, we show that the SLX4 complex is a SUMO E3 ligase that SUMOylates SLX4 itself and the XPF subunit of the DNA repair/recombination XPF-ERCC1 endonuclease. This SLX4-dependent activity is mediated by a remarkably specific interaction between SLX4 and the SUMO-charged E2 conjugating enzyme UBC9 and relies not only on newly identified SUMO-interacting motifs (SIMs) in SLX4 but also on its BTB domain. In contrast to its ubiquitin-binding UBZ4 motifs, SLX4 SIMs are dispensable for its DNA interstrand crosslink repair functions. Instead, while detrimental in response to global replication stress, the SUMO E3 ligase activity of the SLX4 complex is critical to prevent mitotic catastrophe following common fragile site expression.

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Section: Slx4 a New Type Of Sumo E3 Ligase?supporting

confidence: 53%

The SLX4 Complex Is a SUMO E3 Ligase that Impacts on Replication Stress Outcome and Genome Stability

et al. 2015

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“…Similarly, a DNA binding mutation in the PCNA-like UL44 protein also impairs its sumoylation [31]. In some cases, DNA repair engagement, rather than simply DNA association, is required for sumoylation, as seen for the yeast Rad1 nuclease and human FANCI and FANCD2 proteins [32, 33]. Taken together, these new findings in different organisms suggest that DNA association and repair engagement are conserved requirements for the sumoylation of multiple DNA metabolism proteins.…”

Section: Low Level Of Substrate Sumoylation Can Be Linked To On-site mentioning

confidence: 99%

“…First, sumoylation levels of some of these proteins increase in situations when they are more active. For example, the sumoylation of several DNA repair proteins is induced when cells are treated with the DNA damaging agents that elicit repair activities from that protein, with higher genotoxin dosage having a stronger effect [6, 33, 36]. Along the same lines, sumoylation levels of some substrates peak in the cell cycle stage at which they are most active [15, 37, 38].…”

Section: Low Level Of Substrate Sumoylation Can Be Linked To On-site mentioning

confidence: 99%

“…Along the same lines, sumoylation levels of some substrates peak in the cell cycle stage at which they are most active [15, 37, 38]. Second, the absence of upstream DNA repair factors reduces the sumoylation of downstream proteins in homologous recombination (HR), nucleotide excision repair (NER), and inter-strand crosslink repair [5, 6, 32, 33, 39]. Third, substrates are hyper-sumoylated when their DNA association is prolonged, either by mutation of their catalytic sites or inhibition of downstream reactions.…”

Section: Low Level Of Substrate Sumoylation Can Be Linked To On-site mentioning

confidence: 99%

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SUMO-mediated regulation of DNA damage repair and responses

Sarangi

Zhao

2015

Trends in Biochemical Sciences

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127

113

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Sumoylation plays important roles during DNA damage repair and responses. Recent broad-scope and substrate-based studies have shed light on the regulation and significance of sumoylation during these processes. An emerging paradigm is that sumoylation of many DNA metabolism proteins is controlled by DNA engagement. Such “on-site modification” can explain low substrate modification levels and has important implications in sumoylation mechanisms and effects. New studies also suggest that sumoylation can regulate a process through an ensemble effect or via major substrates. Additionally, we describe new trends in the functional effects of sumoylation, such as bi-directional changes in biomolecule binding and multi-level coordination with other modifications. These emerging themes and models will stimulate our thinking and research in sumoylation and genome maintenance.

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“…A number of studies have identified roles for SUMO in modulating DNA repair (89–98). The work presented here suggests SUMO-mediated regulation could extend to the evolutionarily conserved BER pathway.…”

Section: Discussionmentioning

confidence: 99%

Identification of SUMO modification sites in the base excision repair protein, Ntg1

et al. 2016

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DNA damaging agents are a constant threat to genomes in both the nucleus and the mitochondria. To combat this threat, a suite of DNA repair pathways cooperate to repair numerous types of DNA damage. If left unrepaired, these damages can result in the accumulation of mutations which can lead to deleterious consequences including cancer and neurodegenerative disorders. The base excision repair (BER) pathway is highly conserved from bacteria to humans and is primarily responsible for the removal and subsequent repair of toxic and mutagenic oxidative DNA lesions. Although the biochemical steps that occur in the BER pathway have been well defined, little is known about how the BER machinery is regulated. The budding yeast, Saccharomyces cerevisiae is a powerful model system to biochemically and genetically dissect BER. BER is initiated by DNA N-glycosylases, such as S. cerevisiae Ntg1. Previous work demonstrates that Ntg1 is post-translationally modified by SUMO in response to oxidative DNA damage suggesting that this modification could modulate the function of Ntg1. In this study, we mapped the specific sites of SUMO modification within Ntg1 and identified the enzymes responsible for sumoylating/desumoylating Ntg1. Using a non-sumoylatable version of Ntg1, ntg1ΔSUMO, we performed an initial assessment of the functional impact of Ntg1 SUMO modification in the cellular response to DNA damage. Finally, we demonstrate that, similar to Ntg1, the human homologue of Ntg1, NTHL1, can also be SUMO-modified in response to oxidative stress. Our results suggest that SUMO modification of BER proteins could be a conserved mechanism to coordinate cellular responses to DNA damage.

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Sumoylation of the Rad1 nuclease promotes DNA repair and regulates its DNA association

Cited by 25 publications

References 80 publications

The SLX4 Complex Is a SUMO E3 Ligase that Impacts on Replication Stress Outcome and Genome Stability

The SLX4 Complex Is a SUMO E3 Ligase that Impacts on Replication Stress Outcome and Genome Stability

SUMO-mediated regulation of DNA damage repair and responses

Identification of SUMO modification sites in the base excision repair protein, Ntg1

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