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DNA damage response and genome stability: The role of ATM, ATR and the Mre11 complex

Objective

Chromosomal DNA is continuously subjected to exogenous and endogenous damaging insults. In the presence of DNA damage cells activate a multi-faceted checkpoint response that delays cell cycle progression and promotes DNA repair. Failures in this response lead to genomic instability, the main feature of cancer cells. Several cancer-prone human syndromes including the Ataxia teleangiectasia (A-T), the A-T Like Disorder (ATLD) and the Seckel Syndrome reflect defects in the specific genes of the DNA damage response such as ATM, MRE11 and ATR. DNA damage response pathways are poorly understood at biochemical level in vertebrate organisms. We have established a cell-free system based on Xenopus laevis egg extract to study molecular events underlying DNA damage response. This is the first in vitro system that recapitulates different aspects of the DNA damage response in vertebrates. Using this system we propose to study the biochemistry of the ATM, ATR and the Mre11 complex dependent DNA damage response. In particular we will: 1) Dissect the signal transduction pathway that senses DNA damage and promotes cell cycle arrest and DNA damage repair; 2) Analyze at molecular level the role of ATM, ATR, Mre11 in chromosomal DNA replication and mitosis during normal and stressful conditions; 3) Identify substrates of the ATM and ATR dependent DNA damage response using an innovative screening procedure.

Field of science

  • /natural sciences/biological sciences/biochemistry
  • /medical and health sciences/clinical medicine/oncology/cancer
  • /natural sciences/biological sciences/genetics and heredity/genome

Call for proposal

ERC-2007-StG
See other projects for this call

Funding Scheme

ERC-SG - ERC Starting Grant

Host institution

CANCER RESEARCH UK LBG
Address
St John Street 407 Angel Building
EC1V 4AD London
United Kingdom
Activity type
Research Organisations
EU contribution
€ 1 000 000
Principal investigator
Vincenzo Costanzo (Dr.)
Administrative Contact
Holly Elphinstone (Ms.)

Beneficiaries (1)

CANCER RESEARCH UK LBG
United Kingdom
EU contribution
€ 1 000 000
Address
St John Street 407 Angel Building
EC1V 4AD London
Activity type
Research Organisations
Principal investigator
Vincenzo Costanzo (Dr.)
Administrative Contact
Holly Elphinstone (Ms.)