PubMed Health⌕ Search
Home/Archive/PubMed

PubMed · 16533929

Cellular response to DNA damage.

Johnny Kao·Barry S Rosenstein·Sheila Peters·Michael T Milano·Stephen J Kron
View original source ↗Export metadata ↓

Abstract

Eukaryotic cells, from yeast to man, possess evolutionarily conserved mechanisms to accurately and efficiently repair the overwhelming majority of DNA damage, thereby ensuring genomic integrity. Important repair pathways include base excision repair, nucleotide excision repair, mismatch repair, non-homologous end-joining, and homologous recombination. Defects in DNA repair processes generally result in susceptibility to cancer and, often, abnormalities in multiple organ systems. While signal transduction pathways have been intensely studied, epigenetic changes occurring in response to DNA damage are rapidly increasing in importance. Effective radiation and chemotherapy sensitization could result from selective inhibition of DNA repair in tumor cells. DNA damage repair is a dynamic field of research where the fruits of basic research often have important clinical implications.

Explore related subjects

DNADNA DamageDNA RepairHistonesHumansModels, MolecularNeoplasmsProtein ConformationRecombination, GeneticSignal TransductionJournal ArticleReview

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Johnny Kao, Barry S Rosenstein, Sheila Peters, Michael T Milano, Stephen J Kron. 2005. Cellular response to DNA damage.. https://doi.org/10.1196/annals.1363.012

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related citations

PubMed2026

VIPR RNA-guided DNA recognition by noncontiguous geometric triplex formation.

Viral interference programmable repeat (VIPR) systems use a noncontiguous code for RNA-guided transcriptional silencing. How the Vipr protein and a VIPR RNA (vrRNA) comprising alternating GGY and NN segments achieve precise DNA targeting is unknown. Here, we present 21 cryo-electron microscopy structures that help explain the mechanism of target engagement. Vipr protomers oligomerize along the vrRNA to form a right-handed helical filament, sequestering each GGY motif and positioning the adjacent NN bases for target base pairing. DNA binding, in which every third nucleotide is skipped, results in a gapped vrRNA-DNA hybrid helix that encircles the nontarget DNA strand to form a geometric triplex. These findings suggest that triplex-mediated target-strand handoff could enable noncontiguous and programmable RNA-guided DNA recognition in VIPR systems.

DNA↗
PubMed2026

Caloric restriction modulates genome-wide somatic mutation in mice.

Somatic mutations accumulate throughout life in every cell, and this process constitutes one of the hallmarks of aging-genomic instability. Caloric restriction (CR) has been shown to extend lifespan across diverse species. Using high-fidelity duplex DNA sequencing of bulk liver, bulk kidney, hepatocytes, and cerebellar neurons, we found that CR in mice reduces genome-wide somatic mutation burdens across multiple tissues and cell types. CR reduced both substitution and insertion/deletion burdens, with the magnitude of these effects varying across sample types. CR also decreased the activity of the enigmatic single-base substitution (SBS) mutational process SBS5 that gives rise to most mutations in mammals. Surprisingly, the mutation burden reduction from CR was greatest in transcriptionally inactive regions. This work illuminates links between diet, aging, and genomic integrity and establishes genomic integrity as a modifiable axis of aging.

DNA↗
PubMed2026

Maternal DNA repair safeguards genome stability during the oocyte-to-embryo transition.

De novo mutations are a major source of genetic variation and disease risk, yet the developmental timing and mechanisms underlying their origin require further investigation. While germ cells have traditionally been considered the primary source of these mutations, increasing evidence suggests that a substantial fraction arise after fertilization. Here, we investigated the role of maternal DNA repair in shaping mutagenesis during this critical window by using a mouse model with oocyte-specific disruption of the homologous recombination factor RAD51 and a combination of cellular and molecular analyses. Loss of maternal RAD51 led to the accumulation of DNA double-strand breaks in oocytes without impairing their growth, meiotic maturation, or fertilization competence. In contrast, embryos derived from RAD51-deficient oocytes exhibited increased DNA damage and developmental delay during early cleavage stages. Whole-genome sequencing revealed a significant increase in de novo variants in offspring, the majority displaying intermediate allele frequencies consistent with post-zygotic mosaic mutations. These findings confirm that maternal DNA repair safeguards genome stability across the oocyte-to-embryo transition and identify early embryogenesis as a major source of de novo mutations, with implications for reproductive biology and the origins of genetic diseases.

DNA↗