Signaling networks in UV-induced stress response
1 PhD project offered in the IPP summer call 2019
Living organisms are exposed to ultraviolet (UV) radiation from sunlight that triggers the formation of bulky photoproducts in the genome. UV-induced DNA lesions are recognized and repaired by the nucleotide-excision repair (NER) pathway in mammalian cells. Excessive exposure to UV radiation or mutations in NER factors results in genomic instability that can lead to the development of melanoma and premature aging. Signaling induced by different protein kinases plays a central role in the cellular response to UV light. We are employing quantitative mass spectrometry-based proteomics, genomics and biochemistry to identify protein factors and mechanisms that play a role in UV-induced stress response.
PhD Project: Kinase-dependent signaling networks in UV-induced stress response
We have recently shown that in human cells p38 MAP kinase phosphorylates protein complexes that control transcriptional elongation including the negative elongation factor (NELF) complex. The p38-dependent phosphorylation of the NELF complex affects its protein interaction profile and leads to changes in transcriptional elongation that promote genome stability and cellular survival after UV damage (Borisova et al., 2018).
In this PhD project, we aim to provide further insights into phosphorylation signaling networks and gene regulatory mechanisms that play a role in the UV-induced stress response. We will combine mass spectrometry-based phosphoproteomics with nascent RNA sequencing to interrogate protein signaling and transcription changes induced by UV, respectively. We will use human keratinocytes as model system. In addition, we will extend our studies to zebrafish embryos and adult animals in collaboration with René Ketting, to study the importance of identified mechanisms in the organismal context.
Borisova ME, Voigt A, Tollenaere MAX, Sahu SK, Juretschke T, Kreim N, Mailand N, Choudhary C, Bekker-Jensen S, Akutsu M, Wagner SA, Beli P. p38-MK2 signaling axis regulates RNA metabolism after UV-light-induced DNA damage. Nat Commun. 2018 Mar 9;9(1):1017.
Gregersen LH, Svejstrup JQ. The Cellular Response to Transcription-Blocking DNA Damage. Trends Biochem Sci. 2018 May;43(5):327-341.
Borisova ME, Wagner SA, Beli P. Mass Spectrometry-Based Proteomics for Quantifying DNA Damage-Induced Phosphorylation. Methods Mol Biol. 2017;1599:215-227.