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Transcription and the maintenance of genome integrity

Objective

Maintaining genome integrity is crucial, especially in protein-encoding genes. DNA damage in genes can give rise to harmful mutations, but it can also directly obstruct the progress of transcribing RNA polymerase II (RNAPII), thereby blocking gene expression. Not surprisingly, repair pathways have evolved that specifically target lesions that stop RNAPII during its journey across a gene, so-called transcription-coupled repair pathways. As an alternative and ¿last resort¿, damage-stalled RNAPII can also be permanently removed by ubiquitylation/degradation, clearing the gene for repair by other means. Together, transcription-coupled repair and RNAPII ubiquitylation constitute an essential axis in the response to DNA damage.
Conversely, while transcription is essential and therefore protected by a variety of mechanisms, it also itself comes at a cost for genome integrity. For example, high levels of transcription are correlated with breaks at fragile chromosome sites, mutagenesis and elevated levels of DNA recombination. Research into how the genome-destabilizing effects of transcription are minimized is still at an early stage, but insight into this research area is essential for our general appreciation of the regulatory mechanisms at play in the interface between transcription and other DNA-related processes, as well as for the understanding of processes underlying genome instability.
This proposal describes how funding from the ERC will enable us to use a multi-disciplinary approach to shed new light on fundamental and disease-relevant processes, which are crucial for maintaining genome integrity during active transcription.

Call for proposal

ERC-2010-AdG_20100317
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Host institution

THE FRANCIS CRICK INSTITUTE LIMITED
Address
1 Midland Road
NW1 1AT London
United Kingdom
Activity type
Research Organisations
EU contribution
€ 1 950 000
Principal investigator
Jesper Qualmann Svejstrup (Dr.)
Administrative Contact
Stéphane Maikovsky (Mr.)

Beneficiaries (2)

THE FRANCIS CRICK INSTITUTE LIMITED
United Kingdom
EU contribution
€ 1 950 000
Address
1 Midland Road
NW1 1AT London
Activity type
Research Organisations
Principal investigator
Jesper Qualmann Svejstrup (Dr.)
Administrative Contact
Stéphane Maikovsky (Mr.)
CANCER RESEARCH UK LBG

Participation ended

United Kingdom
Address
St John Street 407 Angel Building
EC1V 4AD London
Activity type
Research Organisations
Administrative Contact
Holly Elphinstone (Ms.)