Dataset Information

Exome sequencing identifies novel mutation signatures of UV radiation and trichostatin A in primary human keratinocytes.

ABSTRACT: Canonical ultraviolet (UV) mutation type and spectra are traditionally defined by direct sequencing-based approaches to map mutations in a limited number of representative DNA elements. To obtain an unbiased view of genome wide UV mutation features, we performed whole exome-sequencing (WES) to profile single nucleotide substitutions in UVB-irradiated primary human keratinocytes. Cross comparison of UV mutation profiles under different UVB radiation conditions revealed that T?>?C transition was highly prevalent in addition to C?>?T transition. We also identified 5'-ACG-3' as a common sequence motif of C?>?T transition. Furthermore, our analyses uncovered several recurring UV mutations following acute UVB radiation affecting multiple genes including HRNR, TRIOBP, KCNJ12, and KMT2C, which are frequently mutated in skin cancers, indicating their potential role as founding mutations in UV-induced skin tumorigenesis. Pretreatment with trichostatin A, a pan-histone deacetylase inhibitor that renders chromatin decondensation, significantly decreased the number of mutations in UVB-irradiated keratinocytes. Unexpectedly, we found trichostatin A to be a mutagen that caused DNA damage and mutagenesis at least partly through increased reactive oxidation. In summary, our study reveals new UV mutation features following acute UVB radiation and identifies novel UV mutation hotspots that may potentially represent founding driver mutations in skin cancer development.

SUBMITTER: Shen Y

PROVIDER: S-EPMC7080724 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Exome sequencing identifies novel mutation signatures of UV radiation and trichostatin A in primary human keratinocytes.

Shen Yao Y Ha Wootae W Zeng Wangyong W Queen Dawn D Liu Liang L

Scientific reports 20200318 1

Canonical ultraviolet (UV) mutation type and spectra are traditionally defined by direct sequencing-based approaches to map mutations in a limited number of representative DNA elements. To obtain an unbiased view of genome wide UV mutation features, we performed whole exome-sequencing (WES) to profile single nucleotide substitutions in UVB-irradiated primary human keratinocytes. Cross comparison of UV mutation profiles under different UVB radiation conditions revealed that T > C transition was h ...[more]

PMID: 32188867

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Project description:Primary immunodeficiency disorders (PIDs) render patients vulnerable to infection with a wide range of microorganisms and thus provide good in vivo models for the assessment of immune responses during infectious challenges. Priming of the immune system, especially in infancy, depends on different environmental exposures and medical practices. This may determine the timing and phenotype of clinical appearance of immune deficits as exemplified with early exposure to Bacillus Calmette-Guérin (BCG) vaccination and dissemination in combined immunodeficiencies. Varied phenotype expression poses a challenge to identification of the putative immune deficit. Without the availability of genomic diagnosis and data analysis resources and with limited capacity for functional definition of immune pathways, it is difficult to establish a definitive diagnosis and to decide on appropriate treatment. This study describes the use of exome sequencing to identify a homozygous recessive variant in MAP3K14, NIKVal345Met, in a patient with combined immunodeficiency, disseminated BCG-osis, and paradoxically elevated lymphocytes. Laboratory testing confirmed hypogammaglobulinemia with normal CD19, but failed to confirm a definitive diagnosis for targeted treatment decisions. NIKVal345Met is predicted to be deleterious and pathogenic by two in silico prediction tools and is situated in a gene crucial for effective functioning of the non-canonical nuclear factor-kappa B signaling pathway. Functional analysis of NIKVal345Met- versus NIKWT-transfected human embryonic kidney-293T cells showed that this mutation significantly affects the kinase activity of NIK leading to decreased levels of phosphorylated IkappaB kinase-alpha (IKK?), the target of NIK. BCG-stimulated RAW264.7 cells transfected with NIKVal345Met?also presented with reduced levels of phosphorylated IKK?, significantly increased p100 levels and significantly decreased p52 levels compared to cells transfected with NIKWT. Ideally, these experiments would have been conducted in patient-derived immune cells, but we were unable to source these cells from the patient. The functional analysis described in this paper supports previous illustrations of the importance of NIK in human immune responses and demonstrates the involvement of function-altering mutations in MAP3K14 in PIDs. The genomic approach used for this patient demonstrates its value in the diagnosis of an unusual PID and as a tool for detecting rarer mutations to help guide treatment approaches.

Dataset Information

Exome sequencing identifies novel mutation signatures of UV radiation and trichostatin A in primary human keratinocytes.

Publications

Exome sequencing identifies novel mutation signatures of UV radiation and trichostatin A in primary human keratinocytes.

Similar Datasets

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