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Archiv-Übersicht     Angebot Nr. 13426

Angebotsdatum: 17. Mai 2019
Art der Stelle: Doktorarbeit
Fachgebiet: Biologie > Molekularbiologie
Titel des Themas: Role of novel germline mutations in DNA damage response and genome stability regulators identified in childhood cancer

Institut: Institut für Toxikologie
Adresse:
Prof. Thomas Hofmann
Obere Zahlbacher Str.67
55131 Mainz
Tel.:    Fax.:
Bundesland: Rheinland-Pfalz
Homepage:
E-Mail Kontakt: mail

Beschreibung: Location & institution:
Mainz is a beautiful and historical University city with an international academic research environment. The recent establishment of a collaborative research center (CRC/SFB) on DNA repair & genome stability (SFB 1361) at the Johannes Gutenberg University (JGU) of Mainz illustrates the leading position in this research area. The Institute of Toxicology at the University Medical Center at the JGU of Mainz has longstanding research expertise in the function and regulation of the cellular DNA damage response, DNA damage signaling and DNA repair.

Background:
Dysfunction of the DNA damage response is a driving force for genome instability and cancer (Matt & Hofmann, 2016). In childhood cancers, inherited mutations in cancer predisposition genes contribute to a previously underestimated, substantial number of cancer cases. In this collaborative project, whole-exome sequencing (WES) of parent-children trios has been used to identify germline mutations in childhood cancers. Bioinformatic analyses revealed combined germline mutations in Fanconi anemia (FA)/Breast Cancer (BRCA) pathway genes and in a set of genes encoding key DNA damage signaling molecules including the DNA damage-activated kinases ATM, ATR and HIPK2 in children with cancer. In consequence, cells harboring these mutations are expected to reveal functional defects in the DNA damage response and the maintenance of genome stability. Understanding the molecular function of these novel mutations may provide a molecular explanation for development of childhood cancer and may result in the design of new treatment options.

PhD project:
The PhD project is aimed at elucidating the role of specific germline mutations in DNA damage response genes identified by whole exome sequencing in children with cancer.
The work program includes a broad spectrum of techniques from cell biology, molecular biology, biochemistry and molecular genetics including molecular cloning and expression of the mutant versions identified in childhood cancer, generation and functional analysis of cell models using Crisp/Cas9-mediated gene editing, molecular characterization of the mutated versions using automated immunofluorescence-based DNA damage foci analysis, mass spectrometry-based interaction analysis, FACS-based cell cycle and DNA repair pathway choice assays, life-cell imaging-based dynamic localization studies and cell fate analyses in response to genome damage. The methods/techniques required for the project are established at the Institute of Toxicology and/or will be performed in close collaboration with the DNA damage repair analyses Z-platform of the SFB1361 “Regulation of DNA repair and genome stability”.

Qualification:
We are seeking for a highly motivated PhD student to join our enthusiastic and collaborative research environment. Candidates should have demonstrated outstanding performance during their undergraduate studies. We expect a high degree of self-motivation, enthusiasm for multidisciplinary scientific research as well as good communication skills with a very good English and the ability to work in a team.
Methoden:
Anfangsdatum: 17. Mai 2019
Geschätzte Dauer: 3-4 years
Bezahlung: E13/65%
Papers: Kuhlen M, Taeubner J, Brozou T, Wieczorek D, Siebert R and Borckhardt A. (2019) Oncogene 38:1367-1380.

He Y, Roos WP, Wu Q, Hofmann TG and Kaina B (2019). The Siah1-HIPK2-p53Ser46 damage response is involved in telozolomide-induced cell death. Mol Cancer Res. 17: 1129-1141.

Matt S and Hofmann TG (2018). Crosstalk between p53 modifiers at PML bodies. Mol Cell Oncol. 5:e1074335.

Matt,S and Hofmann TG (2016). The DNA damage-induced cell death response: a roadmap to kill cancer cells. Cell Mol Life Sci. 73:2829-50.
Conrad E, Polonio-Vallon T et al. And Hofmann TG (2016). HIPK2 restricts SIRT1 activity upon severe DNA damage by a phosphorylation-based mechanism. Cell Death Differ 23: 110-122.

Abu-Odeh M, Salah Z, Herbel C, Hofmann TG, Aqeilan RI (2014) WWOX, the common fragile site FRA16D gene product, regulates ATM activation and the DNA damage response. Proc Natl. Acad. Sci. 111:E4716-4725.

Bitomsky N, Conrad E, Moritz C, Polonio-Vallon T, Sombroek D, Schultheiss K, Glas C, Greiner V, Herbel C, Mantovani F, del Sal G, Peri F, Hofmann TG (2013) Autophosphorylation and Pin1 binding coordinate DNA damage-induced HIPK2 activation and cell death. Proc Natl. Acad. Sci.110:E4203-4212.

Winter M, Sombroek D, Dauth I, Moehlenbrink J, Scheuermann K, Crone J, Hofmann TG (2008) Control of HIPK2 stability by ubiquitin ligase Siah-1 and checkpoint kinases ATM and ATR. Nature Cell Biology 10:812-824.

Sonstiges:
Application documents:
Please send your CV, University certificates, a letter of intent and names and addresses of three references to Prof. Dr. rer. nat. Thomas Hofmann.

Email: toxicology@unimedizin-mainz.de

WebPage: http://www.unimedizin-mainz.de/toxikologie/uebersicht.html

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