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Atr's role in replication fork progression through damaged dna

Objectif

The integrity of the genome is safeguarded by elaborate signaling mechanisms called checkpoints, which are activated in response to DNA damage or inhibition of chromosome replication. These signaling pathways involve a cascade of protein kinases such as Mec1 and ATR. Mec1 plays a central role in the DNA damage responsive pathways during chromosome replication and is important for the replication fork progression through damaged DNA. In human cells ATR kinase is the apparent Mec1 homologue. The research goal is study the response of the ATR checkpoint kinase to DNA damage during chromosomal replication. ATR will be inhibited with chemical inhibitors and by an innovative, novel genetic strategy. We will develop a system, which allows both transcriptional repression of the ATR gene and hormone-dependent degradation of the ATR protein, which provides a powerful way of inactivating ATR specifically in mammalian cells. The objective is to study the role of ATR in the maintenance of replication fork stability. ATR might mediate the recruitment of DNA capable of replicating past the damaged DNA and we will study its role in the recruitment of tranlesion synthesis apparatus. We will also test if inhibition of ATR prevents the recruitment of DNA damage responsive proteins to stalled forks and explore the alternative possibility that ATR controls the maintenance of replication proteins at the stalled forks. Elucidation of the biological mechanism of action by the ATR checkpoint kinase will add to our understanding of the maintenance of genomic integrity in mammalian cells. My previous work has mainly embraced the fields of molecular and cellular biology, as well as DNA replication and DNA damage response. My new research project allows me to expand into the fields of proteolysis and genetics, and thus gives me with a true learning experience. This combination serves my professional growth by introducing me to new fields without the need to disregard my previous expertise on mammalian systems. Moreover, since Dr. Diffley's laboratory is well familiar with the degron system in yeast and ICRF has extensive mouse genetics and knock-out technology facilities, I will be provided with all the support I need. This fellowship will allow me to learn more about the fascinating field of checkpoints as well as introducing me to new fields of proteolysis and genetics, as thus provides me with the challenge and growth opportunities that I need in order to grow and develop as a scientist.

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Coordinateur

CANCER RESEARCH UK
Contribution de l’UE
Aucune donnée
Adresse
Clare Hall Laboratories, Blanche Lane
EN6 3LD POTTERS BAR
Royaume-Uni

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Coût total
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