Understanding bias in DNA repair

Strick, Térence; Savery, Nigel J.

doi:10.1073/pnas.1701549114

Cited by 5 publications

(6 citation statements)

References 24 publications

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“…In contrast, the regions where the reference strand acts as the antisense strand exhibited a high density of G>A transitions ( Figure 2 C, Figure S7 ). According to the mechanism of transcription-coupled DNA repair, the RNA polymerase stalls at DNA lesions and triggers the assembly of repair complexes during transcription [24] . Hence, a mutation in the antisense strand will more likely be repaired and the mutation profile of the sense strand will better exhibit the mutagenesis.…”

Section: Resultsmentioning

confidence: 99%

Common Postzygotic Mutational Signatures in Healthy Adult Tissues Related to Embryonic Hypoxia

Hong

Zhang

Zhou

et al. 2021

Genomics, Proteomics &Amp; Bioinformatics

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Postzygotic mutations are acquired in normal tissues throughout an individual’s lifetime and hold clues for identifying mutagenic factors. Here, we investigated postzygotic mutation spectra of healthy individuals using optimized ultra-deep exome sequencing of the time-series samples from the same volunteer as well as the samples from different individuals. In blood, sperm, and muscle cells, we resolved three common types of mutational signatures. Signatures A and B represent clock-like mutational processes, and the polymorphisms of epigenetic regulation genes influence the proportion of signature B in mutation profiles. Notably, signature C, characterized by C>T transitions at GpCpN sites, tends to be a feature of diverse normal tissues. Mutations of this type are likely to occur early during embryonic development, supported by their relatively high allelic frequencies, presence in multiple tissues, and decrease in occurrence with age. Almost none of the public datasets for tumors feature this signature, except for 19.6% of samples of clear cell renal cell carcinoma with increased activation of the hypoxia-inducible factor 1 (HIF-1) signaling pathway. Moreover, the accumulation of signature C in the mutation profile was accelerated in a human embryonic stem cell line with drug-induced activation of HIF-1α. Thus, embryonic hypoxia may explain this novel signature across multiple normal tissues. Our study suggests that hypoxic condition in an early stage of embryonic development is a crucial factor inducing C>T transitions at GpCpN sites; and individuals’ genetic background may also influence their postzygotic mutation profiles.

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Section: Resultsmentioning

confidence: 99%

Common Postzygotic Mutational Signatures in Healthy Adult Tissues Related to Embryonic Hypoxia

Hong

Zhang

Zhou

et al. 2021

Genomics, Proteomics &Amp; Bioinformatics

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“…Because the duplex RNA-seq data retained strand information of the molecules, we were able to determine the strand bias for different classes of RNAs. DNA replication and transcription can exert a strand bias on the DNA repair process (Liu et al 2002;Brachman and Kmiec 2004), particularly transcription levels affecting the degree of bias (Strick and Savery 2017). This in turn c a a a a .…”

Section: Overview Of Duplex Rna Distribution and Dynamics In P Falcimentioning

confidence: 99%

The RNA Structurome in the Asexual Blood Stages of Malaria PathogenPlasmodium falciparum

Alvarez

Ospina

Dey

et al. 2020

Preprint

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RNA as an effector of biological functions often adopts secondary and tertiary structural folds. Plasmodium falciparum is a deadly human pathogen responsible for the devastating disease called malaria. In this study, we measured the differential accumulation of RNA secondary structures in coding and noncoding transcripts from the asexual developmental cycle in P. falciparum in human red blood cells. Our comprehensive analysis, combining high-throughput nuclease mapping of RNA structures by duplex RNA-seq, immunoaffinity purification and RNA analysis, collectively measured differentially base-paired RNA regions during the parasite development. Our mapping data not only aligned to a diverse pool of RNAs with known structures but also enabled us to identify new structural RNA regions in the malaria genome. On average, ~71% of the genes with secondary structures are found to be protein coding mRNAs. Mapping pattern of these base-paired RNAs corresponded to all portions of protein-coding mRNAs, including 5- UTR, CDS and 3- UTR. In addition to histone family genes which are known to form secondary structures in their mRNAs, transcripts from genes which are important for transcriptional and post-transcriptional control, such as unique plant-like transcription factor family, ApiAP2, DNA/RNA binding protein family, Alba, ribosomal proteins and eukaryotic initiation factors involved in translational control and the ones important for RBC invasion and cytoadherence also show strong accumulation of duplex RNA reads in various asexual stages. Intriguingly, our study determined a positive relationship between mRNA structural contents and translation efficiency in P. falciparum asexual blood stages, suggesting an essential role of RNA structural changes in malaria gene expression programs.

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“…After recognizing the damaged part, NER removes lesions from the DNA by removing covalently linked damaged bases from the parent DNA chain. During NER, the damaged parts or lesions are recognized by several signaling proteins , including Xeroderma Pigmentosum group A protein (XPA) and Replication Protein A (RPA). − Although the exact mechanism by which these proteins recognize DNA lesions is still not completely and quantitatively characterized, several studies suggest that distortion in the helical structure is the point of recognition. − One class of structural distortion can be found in the double-helical DNA in which noncomplementary nucleotide bases are aligned in the same base-pair step of a duplex DNA . A mismatch can readily be spotted during the replication processes, which makes the recognition of such a type of damage useful.…”

Section: Introductionmentioning

confidence: 99%

“…It is important to understand the complete structure-dynamics-function mechanism of damage recognition by proteins, which is one of the most intensive research fields in cell biology, molecular biology, and biophysics. In recent years, static and ensemble-averaged structural measurements and analysis of protein–DNA recognition complexes by X-ray and cryo-EM have shed light on the complex structures of DNA damage repair, − but the dynamics of the process is demanding further detailed, quantitative, and selective detections and studies.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Probing Protein–DNA Conformational Dynamics in DNA Damage Recognition: Xeroderma Pigmentosum Group A Stabilizes the Damaged DNA-RPA14 Complex by Controlling Conformational Fluctuation Dynamics

Jaiswal

Han

2022

J. Phys. Chem. B

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DNA damage inside biological systems may result in diseases like cancer. One of the major repairing mechanisms is the nucleotide excision repair (NER) that recognizes and repairs the damage caused by several internal and external exposures, such as DNA double-strand distortion due to the chemical modifications. Recognition of lesions is the initial stage of the DNA damage repair, which occurs with the help of several proteins like Replication Protein A (RPA) and Xeroderma Pigmentosum group A (XPA). The recognition process involves complex conformational dynamics of the proteins. Studying the dynamics of damage recognition by these proteins helps us to understand the mechanism and to develop therapeutics to increase the efficiency of recognition. Here, we use single-molecule fluorescence fluctuation measurements of a dye, labeled at a damaged position on DNA, to understand the interaction of the damage site with RPA14 and XPA. Our results suggest that interactive conformational dynamics of RPA14 with damaged DNA is inhomogeneous due to its low affinity for DNA, whereas binding of XPA with the already formed DNA-RPA14 complex may increase the specificity of damage recognition by controlling the conformational fluctuation dynamics of the complex.

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Understanding bias in DNA repair

Cited by 5 publications

References 24 publications

Common Postzygotic Mutational Signatures in Healthy Adult Tissues Related to Embryonic Hypoxia

Common Postzygotic Mutational Signatures in Healthy Adult Tissues Related to Embryonic Hypoxia

The RNA Structurome in the Asexual Blood Stages of Malaria PathogenPlasmodium falciparum

Probing Protein–DNA Conformational Dynamics in DNA Damage Recognition: Xeroderma Pigmentosum Group A Stabilizes the Damaged DNA-RPA14 Complex by Controlling Conformational Fluctuation Dynamics

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