The deSUMOylase SENP2 coordinates homologous recombination and nonhomologous end joining by independent mechanisms

Garvin, Alexander J; Walker, Alexandra K.; Densham, Ruth M; Chauhan, Anoop Singh; Stone, Helen R; Mackay, Hannah L.; Jamshad, Mohammed; Starowicz, Katarzyna; Daza-Martín, Manuel; Ronson, George E.; Lanz, Alexander; Beesley, James; Morris, Joanna R.

doi:10.1101/gad.321125.118

Cited by 38 publications

(46 citation statements)

References 76 publications

(107 reference statements)

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“…A key function of chain-trimming SUMO isopeptidases would therefore be to protect the complexes from polySUMOylation until release should occur. In line with this idea it has been proposed that SENPs are required to restrict an "over before it has begun" repair response (Garvin et al, 2019). Consistent with this scenario SENP6 localizes to sites of DNA damage in response to DNA damaging stimuli.…”

Section: Discussionmentioning

confidence: 78%

SUMO Chains Rule on Chromatin Occupancy

Keiten-Schmitz

Schunck

2020

Front. Cell Dev. Biol.

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The dynamic and reversible post-translational modification of proteins and protein complexes with the ubiquitin-related SUMO modifier regulates a wide variety of nuclear functions, such as transcription, replication and DNA repair. SUMO can be attached as a monomer to its targets, but can also form polymeric SUMO chains. While monoSUMOylation is generally involved in the assembly of protein complexes, multi-or polySUMOylation may have very different consequences. The evolutionary conserved paradigmatic signaling process initiated by multi-or polySUMOylation is the SUMO-targeted Ubiquitin ligase (StUbL) pathway, where the presence of multiple SUMO moieties primes ubiquitylation by the mammalian E3 ubiquitin ligases RNF4 or RNF111, or the yeast Slx5/8 heterodimer. The mammalian SUMO chain-specific isopeptidases SENP6 or SENP7, or yeast Ulp2, counterbalance chain formation thereby limiting StUbL activity. Many facets of SUMO chain signaling are still incompletely understood, mainly because only a limited number of polySUMOylated substrates have been identified. Here we summarize recent work that revealed a highly interconnected network of candidate polySUMO modified proteins functioning in DNA damage response and chromatin organization. Based on these datasets and published work on distinct polySUMO-regulated processes we discuss overarching concepts in SUMO chain function. We propose an evolutionary conserved role of polySUMOylation in orchestrating chromatin dynamics and genome stability networks by balancing chromatin-residency of protein complexes. This concept will be exemplified in processes, such as centromere/kinetochore organization, sister chromatid cohesion, DNA repair and replication.

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Section: Discussionmentioning

confidence: 78%

SUMO Chains Rule on Chromatin Occupancy

Keiten-Schmitz

Schunck

2020

Front. Cell Dev. Biol.

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“…For instance, SENP2 promotes DNA damage signaling through its protease activity to supply or redistribute SUMO molecules, since HR repair has a great need for SUMO conjugates. 50 Genotoxic stress activates SUMOylation of NEMO, which leads to IKK activation, and then activated NFκB promotes the expression of SENP2, which serves as the primary deSUMOylation protease for NEMO, subsequently leading to feedback attenuation of IKK and NFκB activation. 51 The MRN complex contains a single NBS1 protein, a flexible MRE11 dimer and two RAD50 subunits, which maintain the bond between the two ends of the DNA break.…”

Section: Discussionmentioning

confidence: 99%

SUMOylation stabilizes hSSB1 and enhances the recruitment of NBS1 to DNA damage sites

Zhou

et al. 2020

Sig Transduct Target Ther

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Human single-stranded DNA-binding protein 1 (hSSB1) is required for the efficient recruitment of the MRN complex to DNA doublestrand breaks and is essential for the maintenance of genome integrity. However, the mechanism by which hSSB1 recruits NBS1 remains elusive. Here, we determined that hSSB1 undergoes SUMOylation at both K79 and K94 under normal conditions and that this modification is dramatically enhanced in response to DNA damage. SUMOylation of hSSB1, which is specifically fine-tuned by PIAS2α, and SENP2, not only stabilizes the protein but also enhances the recruitment of NBS1 to DNA damage sites. Cells with defective hSSB1 SUMOylation are sensitive to ionizing radiation, and global inhibition of SUMOylation by either knocking out UBC9 or adding SUMOylation inhibitors significantly enhances the sensitivity of cancer cells to etoposide. Our findings reveal that SUMOylation, as a novel posttranslational modification of hSSB1, is critical for the functions of this protein, indicating that the use of SUMOylation inhibitors (e.g., 2-D08 and ML-792) may be a new strategy that would benefit cancer patients being treated with chemo-or radiotherapy.

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“…4B). We also generated two catalytically inactive mutants, SENP1 C603A and SENP2 C548A (40,41). The mutant and WT SENPs were individually coexpressed with GFP-BAF and His-SUMO1 in cells.…”

Section: Sumoylation Of Baf Also Regulates Its Binding To Nuclear Dnamentioning

confidence: 99%

K6-linked SUMOylation of BAF regulates nuclear integrity and DNA replication in mammalian cells

Lin

Wang

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Barrier-to-autointegration factor (BAF) is a highly conserved protein in metazoans that has multiple functions during the cell cycle. We found that BAF is SUMOylated at K6, and that this modification is essential for its nuclear localization and function, including nuclear integrity maintenance and DNA replication. K6-linked SUMOylation of BAF promotes binding and interaction with lamin A/C to regulate nuclear integrity. K6-linked SUMOylation of BAF also supports BAF binding to DNA and proliferating cell nuclear antigen and regulates DNA replication. SENP1 and SENP2 catalyze the de-SUMOylation of BAF at K6. Disrupting the SUMOylation and de-SUMOylation cycle of BAF at K6 not only disturbs nuclear integrity, but also induces DNA replication failure. Taken together, our findings demonstrate that SUMOylation at K6 is an important regulatory mechanism that governs the nuclear functions of BAF in mammalian cells.

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The deSUMOylase SENP2 coordinates homologous recombination and nonhomologous end joining by independent mechanisms

Cited by 38 publications

References 76 publications

SUMO Chains Rule on Chromatin Occupancy

SUMO Chains Rule on Chromatin Occupancy

SUMOylation stabilizes hSSB1 and enhances the recruitment of NBS1 to DNA damage sites

K6-linked SUMOylation of BAF regulates nuclear integrity and DNA replication in mammalian cells

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