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Excision Repair and chromatin interaction dynamics

Objective

"DNA damage is a fact of life. Lesions hamper genome function, induce mutations causing cancer and trigger senescence or cell death contributing to aging. Therefore cells are equipped with a sophisticated defence machinery: DNA Damage Response (DDR) including different repair pathways. Nucleotide excision repair (NER) is versatile repair process, eliminating helix-distorting lesions, e.g. bulky adducts and sun-induced lesions. Very cytotoxic transcription-blocking lesions are removed by a dedicated sub-pathway, transcription-coupled (TC-)NER. The impact of NER is highlighted by 4 disorders: xeroderma pigmentosum (XP), Cockayne syndrome (CS), trichothiodystrophy and UV-sensitive syndrome (UVSS). XP patients are cancer-prone due to global-genome (GG-)NER defects, whereas CS patients, impaired in TC-NER, display progeroid features, which are thought to derive from endogenous oxidative DNA lesions hampering transcription. Consistent with this, CS cells are sensitive to oxidative agents, whereas TC-NER-deficient UVSS patients are not sensitive to oxidative agents and do not display aging features. This implies lesion-specific TC-NER, arguing for distinct operational TC-repair machineries. The relative importance of DDR pathways varies with the type of damage, cell type and stage of development determining onset of cancer and aging pathologies. The challenging ambition of this proposal is to gain in depth insight into the role of NER in protection against cancer and aging by an integral multi-disciplinary approach which includes new mouse models for novel TC-NER genes, live cell and tissue NER kinetic analyses, advanced proteomics and analysis of NER-related chromatin dynamics to dissect cross-talk with other pathways. The strength of this project is the comprehensive strategy, availability of unique tools (e.g. collection of bona fide NER mutant mice), operational top notch technical platforms for all proposed approaches and proven competence and expertise."

Field of science

  • /medical and health sciences/basic medicine/pathology
  • /natural sciences/biological sciences/genetics and heredity/mutation
  • /natural sciences/biological sciences/genetics and heredity/nucleotide
  • /medical and health sciences/clinical medicine/oncology/cancer
  • /natural sciences/biological sciences/genetics and heredity/genome
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins/proteomics

Call for proposal

ERC-2013-ADG
See other projects for this call

Funding Scheme

ERC-AG - ERC Advanced Grant

Host institution

ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM
Address
Dr Molewaterplein 40
3015 GD Rotterdam
Netherlands
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 2 500 000
Principal investigator
Willem Vermeulen (Dr.)
Administrative Contact
Riet Van Zeijl (Mrs.)

Beneficiaries (1)

ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM
Netherlands
EU contribution
€ 2 500 000
Address
Dr Molewaterplein 40
3015 GD Rotterdam
Activity type
Higher or Secondary Education Establishments
Principal investigator
Willem Vermeulen (Dr.)
Administrative Contact
Riet Van Zeijl (Mrs.)