The multi-functional Smc5/6 complex in genome protection and disease

Peng, Xiao; Zhao, Xiaolan

doi:10.1038/s41594-023-01015-6

Cited by 15 publications

(19 citation statements)

References 111 publications

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“…The SMC5/6 complex stands out as the most cryptic eukaryotic SMC complex. It is thought to be implicated in a variety of cellular processes, like genome replication, DNA damage repair, and defense against viral DNA 19 . Unlike the condensin and cohesin complexes, which contain hawk proteins, the SMC5/6 complex contains kite proteins; hawks and kites, however, do not appear to be homologous 20 .…”

Section: Resultsmentioning

confidence: 99%

Shaping up genomes: Prokaryotic roots and eukaryotic diversification of SMC complexes

van Hooff,

Raas,

Tromer

et al. 2024

Preprint

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Across the tree of life, SMC complexes organize, segregate and regulate DNA. In contrast to prokaryotes, which often possess one SMC complex, eukaryotes usually have four such complexes. This expanded set is involved in managing the considerably larger nuclear genomes of eukaryotes, which are distributed across multiple chromosomes. Despite their essential functions, SMC complexes exhibit variations across model eukaryotes, suggesting an even greater variety of these complexes that remains unexplored. Here, we aimed to uncover the diversity and evolution of SMC complexes across eukaryotes, and their deeper, prokaryotic evolutionary origins. For this, we conducted in-depth comparative genomic and phylogenetic analyses of SMC complexes. We show that the last eukaryotic common ancestor (LECA) likely had fully-fledged versions of all four complexes and that the condensin II complex was later lost at least 30 times in eukaryotes. We report evidence that proteins previously designated as functional analogs in various model organisms (e.g., Sororin, Securin, Nse5 and Nse6) are in fact genuine orthologs. Finally, we traced the prokaryotic origins of these complexes and propose that a single SMC complex duplicated in an early archaeon. Altogether, we provide a comprehensive overview of eukaryotic SMC complex diversity and evolution, both addressing and generating questions about their functioning in ancestral and contemporary organisms.

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Section: Resultsmentioning

confidence: 99%

Shaping up genomes: Prokaryotic roots and eukaryotic diversification of SMC complexes

van Hooff,

Raas,

Tromer

et al. 2024

Preprint

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“…Mass spectrometry revealed a set of proteins with 2 clusters including proteins involved in regulation of SUMOylation, which are known targets of RNF4 ( 34 ), and several members of the SMC5/6 complex ( Supplemental Table 5 and Supplemental Figure 4 , E and F). The SMC5/6 complex is regulated by SUMOylation, and contributes to replication fork stability and regulation of recombination ( 39 ). SUMOylated SMC5 and SMC6 were significantly enriched in chromatin from Rnf4 Δ/Δ cells relative to WT ( Figure 4E ).…”

Section: Resultsmentioning

confidence: 99%

“…The SMC5/6 complex is known to prevent the accumulation of toxic recombination intermediates that appear at stalled replication forks ( 39 , 40 ). We observed that knockdown of RNF4 using multiple different siRNAs in U2OS EJ-DR reporter cells caused an increase in the rate of HR-mediated repair of DNA double-strand breaks ( Supplemental Figure 5A ).…”

Section: Resultsmentioning

confidence: 99%

“…This process involves the prevention of intertwining of sister chromatid molecules behind the replication fork. Depletion of SMC5/6 in yeast causes a block in replication at the ribosomal DNA array ( 39 ). The SMC5/6 complex furthermore physically interacts with FANCI and FANCD2 in mammalian cells ( 72 ); therefore defects in the regulation of SMC5/6 may account for the reduced accumulation of FANCI and FANCD2 at replication forks in Rnf4 Δ/Δ cells.…”

Section: Discussionmentioning

confidence: 99%

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RNF4 sustains Myc-driven tumorigenesis by facilitating DNA replication

Her,

Zheng,

Bunting

2024

Journal of Clinical Investigation

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“…The SMC5/6 complex has structural and catalytic functions, all of which have been demonstrated to play roles in genome stability (Aragon 2018;Peng and Zhao 2023).…”

Section: Discussionmentioning

confidence: 99%

The SMC5/6 complex prevents genotoxicity upon APOBEC3A-mediated replication stress

O’Leary,

Hansen,

Fingerman

et al. 2023

Preprint

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Mutational patterns consistent with the activity of the APOBEC3 cytidine deaminases are evident in more than half of human cancer genomes. APOBEC3-mediated mutagenesis is genotoxic when uncontrolled due to accumulation of base mutations, replication stress, and DNA breaks. In particular, the APOBEC3A family member is a potent enzyme with nuclear localization that causes substantial DNA damage in experimental systems and human tumors. However, the spectrum of genome-protective mechanisms that ensure genome stability in cells with active APOBEC3A is unknown. Through a genome-wide functional screen, we identify the Structural Maintenance of Chromosomes 5/6 (SMC5/6) complex as essential for cell viability when APOBEC3A is expressed. Cells depleted of SMC5/6 incurred substantial DNA damage when APOBEC3A was active, as reflected by increased DNA breaks, DNA damage signaling, and defective proliferation. We observed an absence of APOBEC3A mutagenesis in human tumors with dysfunction of SMC5/6, consistent with synthetic lethality. APOBEC3A is known to act on ssDNA at replication forks. We observed increased DNA damage in replicating cells in the absence of SMC5/6, suggestive of replication forks as a source of DNA breaks. We interrogated replication fork dynamics by DNA fiber spreading and found a consistent increase in the length of replication tracks upon APOBEC3A activity across multiple cell lines. Increased replication fork length was dependent on Primpol, consistent with a repriming mechanism downstream of APOBEC3A-induced lesions. Loss of SMC5/6 resulted in abrogation of fork elongation in cells with active APOBEC3A, along with increased DNA breaks. Our findings indicate that increased length of replication forks in response to APOBEC3A is a genome-protective response and is dependent on intact SMC5/6. Therefore, SMC5/6 may be a therapeutic vulnerability in tumors in which APOBEC3A is active.

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The multi-functional Smc5/6 complex in genome protection and disease

Cited by 15 publications

References 111 publications

Shaping up genomes: Prokaryotic roots and eukaryotic diversification of SMC complexes

Shaping up genomes: Prokaryotic roots and eukaryotic diversification of SMC complexes

RNF4 sustains Myc-driven tumorigenesis by facilitating DNA replication

The SMC5/6 complex prevents genotoxicity upon APOBEC3A-mediated replication stress

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