SUMO Modification Regulates BLM and RAD51 Interaction at Damaged Replication Forks

Ouyang, Karen; Woo, Leslie L.; Zhu, Jianmei; Huo, Dezheng; Matunis, Michael J.; Ellis, Nathan A.

doi:10.1371/journal.pbio.1000252

Cited by 113 publications

(140 citation statements)

References 63 publications

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“…Indeed, recent studies have highlighted roles for post-translational modifications (PTMs) of BLM, including phosphorylation, SUMOylation, and ubiquitination, to mediate fine-tuning of its function (for review, see Bohm and Bernstein 2014). Both BLM and Sgs1 are regulated by PTMs, including SUMOylation (Bohm and Bernstein 2014), and some of these modifications have been linked to changes in the localization in response to different types of DNA damage (Eladad et al 2005;Ouyang et al 2009;Bohm et al 2015). However, no reports to date have explained how these modifications lead to the altered localization and whether they affect the intrinsic function of this RecQ helicase.…”

Section: Discussionmentioning

confidence: 99%

Sgs1's roles in DNA end resection, HJ dissolution, and crossover suppression require a two-step SUMO regulation dependent on Smc5/6

et al. 2016

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The RecQ helicase Sgs1 plays critical roles during DNA repair by homologous recombination, from end resection to Holliday junction (HJ) dissolution. Sgs1 has both pro-and anti-recombinogenic roles, and therefore its activity must be tightly regulated. However, the controls involved in recruitment and activation of Sgs1 at damaged sites are unknown. Here we show a two-step role for Smc5/6 in recruiting and activating Sgs1 through SUMOylation. First, auto-SUMOylation of Smc5/6 subunits leads to recruitment of Sgs1 as part of the STR (Sgs1-Top3-Rmi1) complex, mediated by two SUMO-interacting motifs (SIMs) on Sgs1 that specifically recognize SUMOylated Smc5/6. Second, Smc5/6-dependent SUMOylation of Sgs1 and Top3 is required for the efficient function of STR. Sgs1 mutants impaired in recognition of SUMOylated Smc5/6 (sgs1-SIMΔ) or SUMO-dead alleles (sgs1-KR) exhibit unprocessed HJs at damaged replication forks, increased crossover frequencies during double-strand break repair, and severe impairment in DNA end resection. Smc5/6 is a key regulator of Sgs1's recombination functions.

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Section: Discussionmentioning

confidence: 99%

Sgs1's roles in DNA end resection, HJ dissolution, and crossover suppression require a two-step SUMO regulation dependent on Smc5/6

et al. 2016

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“…In vivo evidence that BLM can disrupt RAD51 polymerization has also been reported (12). Recently, SUMOylation of BLM has been shown to regulate its association with RAD51 and its function in HR-mediated repair of damaged replication forks (13). In several models, it has been proposed that BLM restarts replication after the stalling of the fork, thus preventing HR-dependent fork restart (14)(15)(16).…”

Section: Introductionmentioning

confidence: 92%

The Bloom Syndrome Protein Limits the Lethality Associated with RAD51 Deficiency

Bennani-Belhaj

Rouzeau

Buhagiar-Labarchède

et al. 2010

Molecular Cancer Research

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Little is known about the functional interaction between the Bloom's syndrome protein (BLM) and the recombinase RAD51 within cells. Using RNA interference technology, we provide the first demonstration that RAD51 acts upstream from BLM to prevent anaphase bridge formation. RAD51 downregulation was associated with an increase in the frequency of BLM-positive anaphase bridges, but not of BLM-associated ultrafine bridges. Time-lapse live microscopy analysis of anaphase bridge cells revealed that BLM promoted cell survival in the absence of Rad51. Our results directly implicate BLM in limiting the lethality associated with RAD51 deficiency through the processing of anaphase bridges resulting from the RAD51 defect. These findings provide insight into the molecular basis of some cancers possibly associated with variants of the RAD51 gene family. Mol Cancer Res; 8(3); 385-94. ©2010 AACR.

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“…Cells were untreated or treated with 5 Gy and 24 h later, PFGE was performed and relative intensity of DNA breakage was determined, as described earlier. 44 Histology and Fragel Assay. Rnf4 þ / þ and Rnf4 h/h littermate mice were left untreated or treated with IR (5 Gy).…”

Section: Apoptosis (Facs Analysis)mentioning

confidence: 99%

RNF4 is required for DNA double-strand break repair in vivo

et al. 2012

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Unrepaired DNA double-strand breaks (DSBs) cause genetic instability that leads to malignant transformation or cell death. Cells respond to DSBs with the ordered recruitment of signaling and repair proteins to the sites of DNA lesions. Coordinated protein SUMOylation and ubiquitylation have crucial roles in regulating the dynamic assembly of protein complexes at these sites. However, how SUMOylation influences protein ubiquitylation at DSBs is poorly understood. We show herein that Rnf4, an E3 ubiquitin ligase that targets SUMO-modified proteins, accumulates in DSB repair foci and is required for both homologous recombination (HR) and non-homologous end joining repair. To establish a link between Rnf4 and the DNA damage response (DDR) in vivo, we generated an Rnf4 allelic series in mice. We show that Rnf4-deficiency causes persistent ionizing radiationinduced DNA damage and signaling, and that Rnf4-deficient cells and mice exhibit increased sensitivity to genotoxic stress. Mechanistically, we show that Rnf4 targets SUMOylated MDC1 and SUMOylated BRCA1, and is required for the loading of Rad51, an enzyme required for HR repair, onto sites of DNA damage. Similarly to inactivating mutations in other key regulators of HR repair, Rnf4 deficiency leads to age-dependent impairment in spermatogenesis. These findings identify Rnf4 as a critical component of the DDR in vivo and support the possibility that Rnf4 controls protein localization at DNA damage sites by integrating SUMOylation and ubiquitylation events.

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SUMO Modification Regulates BLM and RAD51 Interaction at Damaged Replication Forks

Abstract: SUMO modification of BLM controls the switch between BLM's pro- and anti-recombinogenic roles in homologous recombination following DNA damage during replication.

Cited by 113 publications

References 63 publications

Sgs1's roles in DNA end resection, HJ dissolution, and crossover suppression require a two-step SUMO regulation dependent on Smc5/6

Sgs1's roles in DNA end resection, HJ dissolution, and crossover suppression require a two-step SUMO regulation dependent on Smc5/6

The Bloom Syndrome Protein Limits the Lethality Associated with RAD51 Deficiency

RNF4 is required for DNA double-strand break repair in vivo

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