Single-molecule studies of high-mobility group B architectural DNA bending proteins

Murugesapillai, Divakaran; McCauley, Micah J.; Maher, L. James; Williams, Mark C.

doi:10.1007/s12551-016-0236-4

Cited by 33 publications

(56 citation statements)

References 124 publications

(238 reference statements)

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“…A total of 72,201,113 raw reads (35,207,345 for SAMP8 and 36,993,768 for SAMR1) were generated. After removal of low-quality and adapter sequences, 71,044,988 clean reads (36,446,427 for SAMR1 and 34,598,561 for SAMP8) were obtained. We filtered the preceding results based on length (18-35 nt).…”

Section: Overview Of Mirna-seqmentioning

confidence: 99%

Characterization of circRNA-Associated-ceRNA Networks in a Senescence-Accelerated Mouse Prone 8 Brain

et al. 2017

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Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. Although many researchers have attempted to explain the origins of AD, developing an effective strategy in AD clinical therapy is difficult. Recent studies have revealed a potential link between AD and circRNA-associated-ceRNA networks. However, few genome-wide studies have identified the potential circRNA-associated-ceRNA pairs involved in AD. In this study, we systematically explored the circRNA-associated-ceRNA mechanism in a 7-month-old senescence-accelerated mouse prone 8 (SAMP8) model brain through deep RNA sequencing. We obtained 235 significantly dysregulated circRNA transcripts, 30 significantly dysregulated miRNAs, and 1,202 significantly dysregulated mRNAs. We then constructed the most comprehensive circRNA-associated-ceRNA networks in SAMP8 brain. GO analysis revealed that these networks were involved in regulating the development of AD from various angles, for instance, axon terminus (GO: 0043679) and synapse (GO: 0045202). Following rigorous selection, we discovered that the circRNA-associated-ceRNA networks in this AD mouse model were mainly involved in the regulation of Aβ clearance (Hmgb2) and myelin function (Dio2). This research is the first to provide a systematic dissection of circRNA-associated-ceRNA profiling in SAMP8 mouse brain. The selected circRNA-associated-ceRNA networks can profoundly affect the diagnosis and therapy of AD in the future.

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Section: Overview Of Mirna-seqmentioning

confidence: 99%

Characterization of circRNA-Associated-ceRNA Networks in a Senescence-Accelerated Mouse Prone 8 Brain

et al. 2017

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“…TFAM belongs to the high-mobility-group (HMG) box family of DNA binding proteins (6,7), and consists of two HMG box domains (HMG1 and HMG2) separated by a linker, coupled to a C-terminal tail via HMG2 (Figure 1). TFAM is essential for initiating transcription of mitochondrial DNA (mtDNA) by specifically recognizing the light-strand and heavy-strand promoters of the mitochondrial genome (8–12).…”

Section: Introductionmentioning

confidence: 99%

Acetylation and phosphorylation of human TFAM regulate TFAM–DNA interactions via contrasting mechanisms

King

Shabestari

Taris

et al. 2018

Nucleic Acids Research

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Mitochondrial transcription factor A (TFAM) is essential for the maintenance, expression and transmission of mitochondrial DNA (mtDNA). However, mechanisms for the post-translational regulation of TFAM are poorly understood. Here, we show that TFAM is lysine acetylated within its high-mobility-group box 1, a domain that can also be serine phosphorylated. Using bulk and single-molecule methods, we demonstrate that site-specific phosphoserine and acetyl-lysine mimics of human TFAM regulate its interaction with non-specific DNA through distinct kinetic pathways. We show that higher protein concentrations of both TFAM mimics are required to compact DNA to a similar extent as the wild-type. Compaction is thought to be crucial for regulating mtDNA segregation and expression. Moreover, we reveal that the reduced DNA binding affinity of the acetyl-lysine mimic arises from a lower on-rate, whereas the phosphoserine mimic displays both a decreased on-rate and an increased off-rate. Strikingly, the increased off-rate of the phosphoserine mimic is coupled to a significantly faster diffusion of TFAM on DNA. These findings indicate that acetylation and phosphorylation of TFAM can fine-tune TFAM–DNA binding affinity, to permit the discrete regulation of mtDNA dynamics. Furthermore, our results suggest that phosphorylation could additionally regulate transcription by altering the ability of TFAM to locate promoter sites.

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“…Further studies, including measurements of the kind reported here, are needed to carefully flesh out the dynamics and distributions of these ubiquitous DNA benders. 99 Our observation of partially bent specific conformations in IHF-DNA complexes also provide structural insights into the underlying mechanism for the "facilitated dissociation"…”

Section: Discussionmentioning

confidence: 74%

Static Kinks or Flexible Hinges: Conformational Distributions of Bent DNA Bound to Integration Host Factor Mapped by Fluorescence Lifetime Measurements

Connolly

Arra

Zvoda

et al. 2018

Preprint

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Gene regulation depends on proteins that bind to specific DNA sites. Such specific recognition often involves severe DNA deformations including sharp kinks. It has been unclear how rigid or flexible these protein-induced kinks are. Here, we investigated the dynamic nature of DNA in complex with integration host factor (IHF), a nucleoid-associated architectural protein known to bend one of its cognate sites (35 base pair H') into a U-turn by kinking DNA at two sites. We utilized fluorescence lifetime based FRET spectroscopy to map the distribution of bent conformations in various IHF-DNA complexes. Our results reveal a surprisingly dynamic specific complex: while 80% of the IHF-H' population exhibited FRET efficiency consistent with the crystal structure, 20% exhibited FRET efficiency indicative of unbent or partially bent DNA. This conformational flexibility is modulated by sequence variations in the cognate site. In another site (H1) that lacks an A-tract of H' on one side of the binding site, the population in the fully U-bent conformation decreased to 36%, as did the extent of bending. A similar decrease in the U-bent population was observed with a single base mutation in H' in a consensus region on the other side. Taken together, these results provide important insights into the finely tuned interactions between IHF and its cognate sites that keep the DNA bent (or not), and yield quantitative data on the dynamic equilibrium between different DNA conformations (kinked or not kinked) that depend sensitively on DNA sequence and deformability. Notably, the difference in dynamics between IHF-H' and IHF-H1 reflects the different roles of these complexes in their natural context, in the phage lambda "intasome" (the complex that integrates phage lambda into the E. coli chromosome).

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Single-molecule studies of high-mobility group B architectural DNA bending proteins

Cited by 33 publications

References 124 publications

Characterization of circRNA-Associated-ceRNA Networks in a Senescence-Accelerated Mouse Prone 8 Brain

Characterization of circRNA-Associated-ceRNA Networks in a Senescence-Accelerated Mouse Prone 8 Brain

Acetylation and phosphorylation of human TFAM regulate TFAM–DNA interactions via contrasting mechanisms

Static Kinks or Flexible Hinges: Conformational Distributions of Bent DNA Bound to Integration Host Factor Mapped by Fluorescence Lifetime Measurements

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