Collection

2015 Nobel Prize in Chemistry

The 2015 Nobel Prize in Chemistry has been awarded to Tomas Lindahl, Paul Modrich and Aziz Sancar "for mechanistic studies of DNA repair".

Lindahl showed that DNA is inherently unstable and requires active repair, and established the role of DNA glycosylase enzymes in base excision repair. Modrich was instrumental in understanding a process called mismatch repair that is involved in repairing errors caused by the DNA replication machinery, while Sancar demonstrated biochemically how enzymes repair damage to DNA from ultraviolet rays, by a process called nucleotide excision repair.

In celebration, our editors have put together this Collection of content from across relevant Nature journals. The Collection illustrates some of the work the laureates have been involved in, as well as research by other important contributors in the DNA repair field. We hope you will enjoy this Collection!

 

Reviews, News and Comment

Nucleotide excision repair (NER) eliminates structurally diverse DNA lesions by repairing helix-distorting damage throughout the genome as well as transcription-blocking lesions. NER defects result in a wide range of disease phenotypes and recent findings have led to a mechanistic model that explains the complex genotype–phenotype correlations of transcription-coupled repair disorders.

Review Article | | Nature Reviews Molecular Cell Biology

The base excision repair (BER) pathway is the most important mechanism for the repair of oxidative DNA damage, which is frequently encountered by host-adapted bacterial pathogens. Here, van der Veen and Tang review DNA repair in the human pathogensMycobacterium tuberculosis, Helicobacter pylori and Neisseria meningitidis, highlighting common and distinct mechanisms.

Review Article | | Nature Reviews Microbiology

Mutagenic processes leave characteristic imprints on the cancer genome that can help to identify the underlying DNA damaging components as well as DNA repair and replicative pathways that are active or disrupted. This Review discusses these mutational signatures according to different classes of mutations and summarizes how different components contribute mechanistically to produce each signature type.

Review Article | | Nature Reviews Genetics

Metabolites and cofactors can be converted to unwanted compounds by promiscuous enzymes and spontaneous chemical reactions. The growing list of enzymes that correct or prevent these reactions, akin to those that combat DNA and protein damage, have important roles in maintaining homeostasis and preventing disease.

Review Article | | Nature Chemical Biology

Damaged DNA must be removed with the utmost precision, as mistakes are costly. The structure of a repair enzyme bound to its substrate provides a welcome clue to how this is achieved.

News & Views | | Nature

Primary Research

The enzyme (6-4) photolyase utilizes blue-light energy to repair DNA damage by cleaving the ultraviolet-induced bond between pyrimidine dimers. Ultrafast spectroscopy has now been used to examine the detailed electron and proton movements during the repair photocycle. Histidine 364 is identified as the crucial residue involved in the rate-limiting step.

Letter | | Nature

Nucleotide excision repair is one of the main pathways for removal of damaged DNA. UvrA, which finds the damaged DNA, has broad specificity. The first crystal structure of UvrA in complex with DNA shows that the UvrA dimer does not contact the lesion directly but instead probes the conformation of the DNA around the modified residue.

Article | | Nature Structural & Molecular Biology

In order to get to their target sites, nearly all DNA binding proteins need to use some form of facilitated diffusion—for example, hopping, jumping, sliding and/or intersegmental transfer. Doing so can be made more difficult when nucleosomes are in their way. But is that really the case? Green and coworkers examine two different mismatch repair proteins using single-molecule microscopy and chromatin curtains and find that one can readily bypass the nucleosome by hopping over it while the other slides along until it is stopped in its tracks by the nucleosome. These types of studies can be used to distinguish between these different types of facilitated diffusion along chromatin.

Article | | Nature Structural & Molecular Biology

MutS scans DNA for mismatches; once a lesion is recognized, MutS initiates a cascade of events that ultimately results in mismatch excision and repair. Now the behavior of MutS on DNA is studied using smFRET, revealing that mismatch recognition triggers ATP binding that switches MutS from a transient scanning clamp to a very stable sliding clamp.

Article | | Nature Structural & Molecular Biology

Eukaryotic MutSβ is a heterodimer composed of Msh2 and Msh3 that recognizes insertion-deletion loops (IDLs) and 3′ overhangs during mismatch repair. Now crystal structures of MutSβ in complex with DNA, containing IDLs of varying lengths, reveal that this complex interacts with its substrate differently than MutSα and bacterial MutS do.

Article | | Nature Structural & Molecular Biology

The bacterial nucleotide excision repair pathway starts with the sensor complex UvrA–UvrB scanning the genome and undergoing conformational change when DNA lesions are detected. Now crystal structures of a UvrA dimer and the UvrA–UvrB complex, along with biochemical analyses, provide insight into these early nucleotide excision repair events.

Article | | Nature Structural & Molecular Biology

DNA damage products influence DNA replication but also may induce stalling or mutagenesis during transcription. A competitive transcription and adduct bypass assay provides a new approach for assessing the transcriptional effects of DNA lesions and links transcriptional arrest of several lesions to nucleotide excision repair pathways.

Article | | Nature Chemical Biology

Certain oxidative DNA lesions adopt altered conformational preferences that lead to mutations during replication. Biochemical and structural data reveal that for formamidopyrimidine lesions, tautomerization and altered base pair geometry in the DNA polymerase active site, rather than changes in glycosidic torsion angle, direct the mutagenicity of these lesions.

Article | | Nature Chemical Biology

Occasionally during DNA replication or repair, a ribonucleotide rather than a deoxyribonucleotide is inserted into the polymer. To reverse this, RNase H2 first cleaves the RNA-DNA junction. This nick is a poor substrate for DNA ligase, however, and an abortive 5′ adenylated end is frequently formed. Scott Williams and colleagues show that the DNA strand-break repair protein aprataxin can remove the 5′ AMP from such RNA-DNA junctions. This RNA-DNA damage response promotes cell survival. Since mutations in the APTX gene encoding aprataxin cause the neurological disorder AOA1 (ataxia oculomotor apraxia-1), these findings suggest that the accumulation of toxic adenylated 5′ ends at ribonucleotides in DNA may cause neurological diseases.

Letter | | Nature

Damaged bases that result from exposure to ultraviolet light interfere with transcription, causing RNA polymerase to stall. UvrD, a DNA helicase required for nucleotide excision repair, can remove such lesions, but its exact role was unknown. Evgeny Nudler and colleagues now show that UvrD is a transcription elongation factor that binds RNA polymerase and promotes its backwards movement when it becomes stalled at a lesion. NusA, another elongation factor, assists in promoting backtracking and helps UvrD to target other nucleotide excision repair factors to the exposed lesion.

Article | | Nature

XPB and XPD are essential helicases with roles in transcription and DNA repair. Genomewide ChIP analysis revealed that XPB and XPD localize to DNA G-quadruplex sequences, including many at the transcriptional start sites of actively expressed genes, suggesting that these alternative DNA structures may serve as genome regulatory elements.

Article | | Nature Chemical Biology

5'-adenylated DNA adducts generated during nucleotide excision repair (NER) are removed by aprataxin to permit DNA end ligation. Now, structural and kinetic analyses reveal that NER enzymes DNA polymerase β and FEN1 can also excise these adducts and thus provide a 'backup' repair pathway for abasic sites.

Brief Communication | | Nature Structural & Molecular Biology

XPC nucleotide excision repair factor is key to starting the repair of diverse helix-distorting DNA lesions caused by environmental insults. Here, the authors propose a kinetic gating mechanism whereby XPC recognizes DNA lesions by preferentially opening damaged sites while readily diffusing away from undamaged sites.

Article | Open Access | | Nature Communications