Thesis topic proposal
The regulation of chromatin structure and nuclear transport during DNA damage repair


Institute: University of Szeged
theoretical medicine
Doctoral School of Multidisciplinary Medical Scienses

Thesis supervisor: Gyula Timinszky
Location of studies (in Hungarian): DNA Damage and Nuclear Dynamics Momentum Research Group Institute of Genetics, Biological Research Center, Szeged
Abbreviation of location of studies: SZBK

Description of the research topic:

Genome integrity is crucial for all living organisms. If damaged DNA is not promptly repaired, the mutations ultimately lead to the development of cancer. Defective repair can also cause immunodeficiency, neurodegenerative disorders and premature ageing. The range of DNA lesions require diverse signaling and repair pathways to shape the DNA damage response. This involves changes in nuclear dynamics including alterations in chromatin structure, nucleocytoplasmic transport and protein activities.
Poly(ADP-ribosyl)ation is one of the earliest post-translational modifications appearing upon DNA damage. Its deregulation impairs DNA repair and is implicated in cancer. We pioneered the identification of macrodomain proteins as key effectors of nuclear ADP-ribosylation. We elucidated how DNA break-induced ADP-ribosylation leads to chromatin relaxation mediated by an oncogenic chromatin remodeler. We also discovered the human enzymes that reverse mono(ADP-ribosyl)ation and identified a novel ATM-induced nuclear export mechanism. Our findings indicate that nuclear dynamics, mRNA metabolism and chromosome organization strongly depend on nuclear ADP-ribosylation reactions and their crosstalk with other signaling pathways, but insight is scant.
Our research goal is to characterize novel molecular mechanisms that regulate the DNA damage response, including nucleocytoplasmic transport, mRNA metabolism and chromatin architecture by using a combination of live-cell imaging, high-content screening and biochemical approaches. Our findings should ultimately advance the understanding of the pathomechanisms underlying the development of diseases due to impaired DNA damage repair and in the future should aid their timely diagnosis and treatment.

Required language skills: English
Number of students who can be accepted: 1

Deadline for application: 2019-12-19

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