Roles of OB-Fold Proteins in Replication Stress

Nguyen, Dan J.M.; Kim, Eugene Y.; Sang, Pau Biak; Chai, Weihang

doi:10.3389/fcell.2020.574466

Cited by 19 publications

(19 citation statements)

References 185 publications

(289 reference statements)

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“…14 This is analogous to the OB-fold family of genome guardians in eukaryotes. 44,45 In eukaryotic cells, many of the proteins functioning in DNA replication, telomere homeostasis, activation of the DNA-damage checkpoint, and DNA repair contain OBfolds. [132][133][134] Not surprisingly, these OB-folds play critical roles in DNA binding, protein complex assembly, and are involved in regulating complex protein-protein interactions.…”

Section: Summary and Future Perspectivesmentioning

confidence: 99%

“…In both SSB‐SSB and SSB‐partner binding, OB‐folds may function as scaffolds for the PXXP‐containing linker, likely contributing to complex stability, as observed for c‐Src 43 . The presence of multiple OB‐folds in SSB and its interactome partners has led to the proposal that this family of proteins is the first family of OB‐fold genome guardians discovered in prokaryotes 14,29,44–46 . The SSB protein and the mechanism of interactome regulation are the topics of this review.…”

Section: Introductionmentioning

confidence: 99%

“…The presence of at least one OB‐fold in multiple interactome members has led to the proposal that the SSB interactome is the first OB‐fold family of genome guardians identified in prokaryotes 14 . This is analogous to the OB‐fold family of genome guardians in eukaryotes 44,45 . In eukaryotic cells, many of the proteins functioning in DNA replication, telomere homeostasis, activation of the DNA‐damage checkpoint, and DNA repair contain OB‐folds 132–134 .…”

Section: Introductionmentioning

confidence: 99%

“…43 The presence of multiple OB-folds in SSB and its interactome partners has led to the proposal that this family of proteins is the first family of OB-fold genome guardians discovered in prokaryotes. 14,29,[44][45][46] The SSB protein and the mechanism of interactome regulation are the topics of this review.…”

mentioning

confidence: 99%

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The mechanism of action of the SSB interactome reveals it is the first OB‐fold family of genome guardians in prokaryotes

Bianco

2021

Protein Science

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The single‐stranded DNA binding protein (SSB) is essential to all aspects of DNA metabolism in bacteria. This protein performs two distinct, but closely intertwined and indispensable functions in the cell. SSB binds to single‐stranded DNA (ssDNA) and at least 20 partner proteins resulting in their regulation. These partners comprise a family of genome guardians known as the SSB interactome. Essential to interactome regulation is the linker/OB‐fold network of interactions. This network of interactions forms when one or more PXXP motifs in the linker of SSB bind to an OB‐fold in a partner, with interactome members involved in competitive binding between the linker and ssDNA to their OB‐fold. Consequently, when linker‐binding occurs to an OB‐fold in an interactome partner, proteins are loaded onto the DNA. When linker/OB‐fold interactions occur between SSB tetramers, cooperative ssDNA‐binding results, producing a multi‐tetrameric complex that rapidly protects the ssDNA. Within this SSB‐ssDNA complex, there is an extensive and dynamic network of linker/OB‐fold interactions that involves multiple tetramers bound contiguously along the ssDNA lattice. The dynamic behavior of these tetramers which includes binding mode changes, sliding as well as DNA wrapping/unwrapping events, are likely coupled to the formation and disruption of linker/OB‐fold interactions. This behavior is essential to facilitating downstream DNA processing events. As OB‐folds are critical to the essence of the linker/OB‐fold network of interactions, and they are found in multiple interactome partners, the SSB interactome is classified as the first family of prokaryotic, oligosaccharide/oligonucleotide binding fold (OB‐fold) genome guardians.

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Section: Summary and Future Perspectivesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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The mechanism of action of the SSB interactome reveals it is the first OB‐fold family of genome guardians in prokaryotes

Bianco

2021

Protein Science

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“…The number of OB-fold proteins has grown rapidly in recent years. The understanding of how they interact with ssDNA [ 100 ] and RNA [ 101 ] has improved considerably. The OB-fold structure is highly dynamic and supports a binding surface for protein–protein interaction and protein-nucleic acid binding.…”

Section: Discussionmentioning

confidence: 99%

Characterization of the Chimeric PriB-SSBc Protein

Lin

Huang

2021

IJMS

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PriB is a primosomal protein required for the replication fork restart in bacteria. Although PriB shares structural similarity with SSB, they bind ssDNA differently. SSB consists of an N-terminal ssDNA-binding/oligomerization domain (SSBn) and a flexible C-terminal protein–protein interaction domain (SSBc). Apparently, the largest difference in structure between PriB and SSB is the lack of SSBc in PriB. In this study, we produced the chimeric PriB-SSBc protein in which Klebsiella pneumoniae PriB (KpPriB) was fused with SSBc of K. pneumoniae SSB (KpSSB) to characterize the possible SSBc effects on PriB function. The crystal structure of KpSSB was solved at a resolution of 2.3 Å (PDB entry 7F2N) and revealed a novel 114-GGRQ-117 motif in SSBc that pre-occupies and interacts with the ssDNA-binding sites (Asn14, Lys74, and Gln77) in SSBn. As compared with the ssDNA-binding properties of KpPriB, KpSSB, and PriB-SSBc, we observed that SSBc could significantly enhance the ssDNA-binding affinity of PriB, change the binding behavior, and further stimulate the PriA activity (an initiator protein in the pre-primosomal step of DNA replication), but not the oligomerization state, of PriB. Based on these experimental results, we discuss reasons why the properties of PriB can be retrofitted when fusing with SSBc.

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De novo MCM6 variants in neurodevelopmental disorders: a recognizable phenotype related to zinc binding residues

et al. 2023

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The minichromosome maintenance (MCM) complex acts as a DNA helicase during DNA replication, and thereby regulates cell cycle progression and proliferation. In addition, MCM-complex components localize to centrosomes and play an independent role in ciliogenesis. Pathogenic variants in genes coding for MCM components and other DNA replication factors have been linked to growth and developmental disorders as Meier–Gorlin syndrome and Seckel syndrome. Trio exome/genome sequencing identified the same de novo MCM6 missense variant p.(Cys158Tyr) in two unrelated individuals that presented with overlapping phenotypes consisting of intra-uterine growth retardation, short stature, congenital microcephaly, endocrine features, developmental delay and urogenital anomalies. The identified variant affects a zinc binding cysteine in the MCM6 zinc finger signature. This domain, and specifically cysteine residues, are essential for MCM-complex dimerization and the induction of helicase activity, suggesting a deleterious effect of this variant on DNA replication. Fibroblasts derived from the two affected individuals showed defects both in ciliogenesis and cell proliferation. We additionally traced three unrelated individuals with de novo MCM6 variants in the oligonucleotide binding (OB)-fold domain, presenting with variable (neuro)developmental features including autism spectrum disorder, developmental delay, and epilepsy. Taken together, our findings implicate de novo MCM6 variants in neurodevelopmental disorders. The clinical features and functional defects related to the zinc binding residue resemble those observed in syndromes related to other MCM components and DNA replication factors, while de novo OB-fold domain missense variants may be associated with more variable neurodevelopmental phenotypes. These data encourage consideration of MCM6 variants in the diagnostic arsenal of NDD.

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Roles of OB-Fold Proteins in Replication Stress

Cited by 19 publications

References 185 publications

The mechanism of action of the SSB interactome reveals it is the first OB‐fold family of genome guardians in prokaryotes

The mechanism of action of the SSB interactome reveals it is the first OB‐fold family of genome guardians in prokaryotes

Characterization of the Chimeric PriB-SSBc Protein

De novo MCM6 variants in neurodevelopmental disorders: a recognizable phenotype related to zinc binding residues

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