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Human MMS21/NSE2 is a SUMO ligase required for DNA repair.

ABSTRACT: DNA repair is required for the genomic stability and well-being of an organism. In yeasts, a multisubunit complex consisting of SMC5, SMC6, MMS21/NSE2, and other non-SMC proteins is required for DNA repair through homologous recombination. The yeast MMS21 protein is a SUMO ligase. Here we show that the human homolog of MMS21 is also a SUMO ligase. hMMS21 stimulates sumoylation of hSMC6 and the DNA repair protein TRAX. Depletion of hMMS21 by RNA interference (RNAi) sensitizes HeLa cells toward DNA damage-induced apoptosis. Ectopic expression of wild-type hMMS21, but not its ligase-inactive mutant, rescues this hypersensitivity of hMMS21-RNAi cells. ATM/ATR are hyperactivated in hMMS21-RNAi cells upon DNA damage. Consistently, hMMS21-RNAi cells show an increased number of phospho-CHK2 foci. Finally, we show that hMMS21-RNAi cells show a decreased capacity to repair DNA lesions as measured by the comet assay. Our findings suggest that the human SMC5/6 complex and the SUMO ligase activity of hMMS21 are required for the prevention of DNA damage-induced apoptosis by facilitating DNA repair in human cells.

SUBMITTER: Potts PR

PROVIDER: S-EPMC1190242 | biostudies-literature | 2005 Aug

REPOSITORIES: biostudies-literature

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Human MMS21/NSE2 is a SUMO ligase required for DNA repair.

Potts Patrick Ryan PR Yu Hongtao H

Molecular and cellular biology 20050801 16

DNA repair is required for the genomic stability and well-being of an organism. In yeasts, a multisubunit complex consisting of SMC5, SMC6, MMS21/NSE2, and other non-SMC proteins is required for DNA repair through homologous recombination. The yeast MMS21 protein is a SUMO ligase. Here we show that the human homolog of MMS21 is also a SUMO ligase. hMMS21 stimulates sumoylation of hSMC6 and the DNA repair protein TRAX. Depletion of hMMS21 by RNA interference (RNAi) sensitizes HeLa cells toward DN ...[more]

PMID: 16055714

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Project description:The post-translational addition of SUMO plays essential roles in numerous eukaryotic processes including cell division, transcription, chromatin organization, DNA repair, and stress defense through its selective conjugation to numerous targets. One prominent plant SUMO ligase is METHYL METHANESULFONATE-SENSITIVE (MMS)-21/HIGH-PLOIDY (HPY)-2/NON-SMC-ELEMENT (NSE)-2, which has been connected genetically to development and endoreduplication. Here, we describe the potential functions of MMS21 through a collection of UniformMu and CRISPR/Cas9 mutants in maize (Zea mays) that display either seed lethality or substantially compromised pollen germination and seed/vegetative development. RNA-seq analyses of leaves, embryos, and endosperm from mms21 plants revealed a substantial dysregulation of the maize transcriptome, including the ectopic expression of seed storage protein mRNAs in leaves and altered accumulation of mRNAs associated with DNA repair and chromatin dynamics. Interaction studies demonstrated that MMS21 associates in the nucleus with the NSE4 and STRUCTURAL MAINTENANCE OF CHROMOSOMES (SMC)-5 components of the chromatin organizer SMC5/6 complex, with in vitro assays confirming that MMS21 will SUMOylate SMC5. Comet assays measuring genome integrity, sensitivity to DNA-damaging agents, and protein versus mRNA abundance comparisons implicated MMS21 in chromatin stability and transcriptional controls on proteome balance. Taken together, we propose that MMS21-directed SUMOylation of the SMC5/6 complex and other targets enables proper gene expression by influencing chromatin structure. Author summary The post-translational addition of SUMO to other proteins by the MMS21 SUMO ligase has been implicated in a plethora of biological processes in plants but the identit(ies) of its targets and the biological consequences of their modification remain poorly resolved. Here, we address this issue by characterizing a collection of maize mms21 mutants using genetic, biochemical, transcriptomic and proteomic approaches. Our results revealed that mms21 mutations substantially compromise pollen germination and seed/vegetative development, dysregulate the maize transcriptome, including the ectopic expression of seed storage protein mRNAs in leaves, increase DNA damage, and alter the proteome/transcriptome balance. Interaction studies showed that MMS21 associates in the nucleus with the NON-SMC-ELEMENT (NSE)-4 and STRUCTURAL MAINTENANCE OF CHROMOSOMES (SMC)-5 components of the chromatin organizer SMC5/6 complex responsible for DNA-damage repair and chromatin accessibility. Our data demonstrate that MMS21 is crucial for plant development likely through its maintenance of DNA repair, balanced transcription, and genome stability.

Dataset Information

Human MMS21/NSE2 is a SUMO ligase required for DNA repair.

Publications

Human MMS21/NSE2 is a SUMO ligase required for DNA repair.

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