Journal article
Chromosomal landscape of UV damage formation and repair at single-nucleotide resolution
Proceedings of the National Academy of Sciences - PNAS, Vol.113(32), pp.9057-9062
08/09/2016
Handle:
https://hdl.handle.net/2376/116702
PMCID: PMC4987812
PMID: 27457959
Abstract
UV-induced DNA lesions are an important contributor to melanomas and other skin cancers. To understand how UV damage leads to cancer-associated mutations, it is important to know how the chromosomal landscape influences initial UV damage formation and repair. We have developed a UV damage mapping procedure to precisely map UV damage throughout the genome. We used this method to map the genome-wide distribution of UV lesions in yeast, a model eukaryote. We found that UV damage is not uniformly distributed, but that damage formation is significantly modulated in a predictable way by nucleosomes and DNA-bound transcription factors. Additionally, genome-wide analysis of removal of UV lesions indicates that repair is significantly inhibited near the center of strongly positioned nucleosomes.
UV-induced DNA lesions are important contributors to mutagenesis and cancer, but it is not fully understood how the chromosomal landscape influences UV lesion formation and repair. Genome-wide profiling of repair activity in UV irradiated cells has revealed significant variations in repair kinetics across the genome, not only among large chromatin domains, but also at individual transcription factor binding sites. Here we report that there is also a striking but predictable variation in initial UV damage levels across a eukaryotic genome. We used a new high-throughput sequencing method, known as CPD-seq, to precisely map UV-induced cyclobutane pyrimidine dimers (CPDs) at single-nucleotide resolution throughout the yeast genome. This analysis revealed that individual nucleosomes significantly alter CPD formation, protecting nucleosomal DNA with an inward rotational setting, even though such DNA is, on average, more intrinsically prone to form CPD lesions. CPD formation is also inhibited by DNA-bound transcription factors, in effect shielding important DNA elements from UV damage. Analysis of CPD repair revealed that initial differences in CPD damage formation often persist, even at later repair time points. Furthermore, our high-resolution data demonstrate, to our knowledge for the first time, that CPD repair is significantly less efficient at translational positions near the dyad of strongly positioned nucleosomes in the yeast genome. These findings define the global roles of nucleosomes and transcription factors in both UV damage formation and repair, and have important implications for our understanding of UV-induced mutagenesis in human cancers.
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Details
- Title
- Chromosomal landscape of UV damage formation and repair at single-nucleotide resolution
- Creators
- Peng Mao - School of Molecular BiosciencesMichael J Smerdon - School of Molecular BiosciencesSteven A Roberts - School of Molecular BiosciencesJohn J Wyrick - School of Molecular Biosciences
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.113(32), pp.9057-9062
- Academic Unit
- Molecular Biosciences, School of
- Publisher
- National Academy of Sciences
- Grant note
- ES022633 / HHS | NIH | National Institute of Environmental Health Sciences (NIEHS) BC141727 / U.S. Department of Defense (DOD) ES002614 / HHS | NIH | National Institute of Environmental Health Sciences (NIEHS)
- Identifiers
- 99900548320101842
- Language
- English
- Resource Type
- Journal article