Transcription-Coupled DNA Repair: From Mechanism to Human Disorder

DNA molecules can adopt a variety of alternative structures. Among these structures are G-quadruplex DNA structures (G4s), which support cellular function by affecting transcription, translation, and telomere maintenance. These structures can also induce genome instability by stalling replication, increasing DNA damage, and recombination events. G-quadruplex-driven genome instability is connected to tumorigenesis and other genetic disorders. In recent years, the connection between genome stability, DNA repair and G4 formation was further underlined by the identification of multiple DNA repair proteins and ligands which bind and stabilize said G4 structures to block specific DNA repair pathways. The relevance of G4s for different DNA repair pathways is complex and depends on the repair pathway itself. G4 structures can induce DNA damage and block efficient DNA repair, but they can also support the activity and function of certain repair pathways. In this review, we highlight the roles and consequences of G4 DNA structures for DNA repair initiation, processing, and the efficiency of various DNA repair pathways.

show abstract

“…MutL has a coordinative and endonucleolytic function during MMR [195][196][197]. MutL binds robustly to parallel G4 structures.…”

Section: Mismatch Repair (Mmr)mentioning

confidence: 99%

The Relevance of G-Quadruplexes for DNA Repair

Linke

Limmer

Juranek

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…DNA lesions in transcribed strands are substrates of transcription-coupled repair (TC-NER) [ 5 ], while elimination of DNA lesions throughout the genome is carried out by global genome repair (GG-NER) [ 6 , 7 ]. Recognition through both sub-pathways ultimately leads to a common mechanism of verification, excision and re-synthesis of the damaged DNA, involving the same set of core NER proteins, including the TFIIH complex, XPA, RPA and the endonucleases XPG and ERCC1-XPF (Fig.…”

Section: Dna Damage Recognition In Nucleotide Excision Repairmentioning

confidence: 99%

Nucleotide excision repair leaves a mark on chromatin: DNA damage detection in nucleosomes

Apelt

Lans

Schärer

et al. 2021

Cell. Mol. Life Sci.

Self Cite

View full text Add to dashboard Cite

Global genome nucleotide excision repair (GG-NER) eliminates a broad spectrum of DNA lesions from genomic DNA. Genomic DNA is tightly wrapped around histones creating a barrier for DNA repair proteins to access DNA lesions buried in nucleosomal DNA. The DNA-damage sensors XPC and DDB2 recognize DNA lesions in nucleosomal DNA and initiate repair. The emerging view is that a tight interplay between XPC and DDB2 is regulated by post-translational modifications on the damage sensors themselves as well as on chromatin containing DNA lesions. The choreography between XPC and DDB2, their interconnection with post-translational modifications such as ubiquitylation, SUMOylation, methylation, poly(ADP-ribos)ylation, acetylation, and the functional links with chromatin remodelling activities regulate not only the initial recognition of DNA lesions in nucleosomes, but also the downstream recruitment and necessary displacement of GG-NER factors as repair progresses. In this review, we highlight how nucleotide excision repair leaves a mark on chromatin to enable DNA damage detection in nucleosomes.

show abstract

“…Similar to NER, new imaging techniques have enabled singlemolecule level imaging for BER enzymes in living cells. While no studies of this nature have been performed with upstream BER enzymes to our knowledge, both prokaryotic Pol I and DNA ligase were studied using PALM at the single molecule scale in live E. coli (Uphoff et al, 2013). In this work, the endogenous proteins were replaced by versions tagged with a photoactivatable mCherry, enabling only a small subset of the fluorescent…”

Section: Visualizing Damage Detection and Handoff By Downstream Ber Enzymesmentioning

confidence: 99%

Searching for DNA Damage: Insights From Single Molecule Analysis

Schaich

Houten

2021

Front. Mol. Biosci.

View full text Add to dashboard Cite

DNA is under constant threat of damage from a variety of chemical and physical insults, such as ultraviolet rays produced by sunlight and reactive oxygen species produced during respiration or inflammation. Because damaged DNA, if not repaired, can lead to mutations or cell death, multiple DNA repair pathways have evolved to maintain genome stability. Two repair pathways, nucleotide excision repair (NER) and base excision repair (BER), must sift through large segments of nondamaged nucleotides to detect and remove rare base modifications. Many BER and NER proteins share a common base-flipping mechanism for the detection of modified bases. However, the exact mechanisms by which these repair proteins detect their damaged substrates in the context of cellular chromatin remains unclear. The latest generation of single-molecule techniques, including the DNA tightrope assay, atomic force microscopy, and real-time imaging in cells, now allows for nearly direct visualization of the damage search and detection processes. This review describes several mechanistic commonalities for damage detection that were discovered with these techniques, including a combination of 3-dimensional and linear diffusion for surveying damaged sites within long stretches of DNA. We also discuss important findings that DNA repair proteins within and between pathways cooperate to detect damage. Finally, future technical developments and single-molecule studies are described which will contribute to the growing mechanistic understanding of DNA damage detection.

show abstract

Transcription-Coupled DNA Repair: From Mechanism to Human Disorder

Cited by 76 publications

References 72 publications

The Relevance of G-Quadruplexes for DNA Repair

The Relevance of G-Quadruplexes for DNA Repair

Nucleotide excision repair leaves a mark on chromatin: DNA damage detection in nucleosomes

Searching for DNA Damage: Insights From Single Molecule Analysis

Contact Info

Product

Resources

About