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Switch recombination: a model system for DNA editing and repair in human lymphocytes with relevance for primary immunodeficiency and cancer formation

Switch recombination: a model system for DNA editing and repair in human lymphocytes with relevance for primary immunodeficiency and cancer formation

Objective

The aim of this project is to try to understand the complex molecular mechanisms involved in DNA editing, repair and recombination during immunoglobulin class switch recombination (CSR) and somatic hypermutation (SHM). We have developed a series of PCR-based assays to study in vivo generated CSR junctions and the pattern of mutations introduced in the immunoglobulin variable region genes in human B cells, allowing us to characterize CSR and SHM in patients with immunodeficiency due to defect(s) in DNA repair/recombination. Novel in vitro CSR assays, based on GFP expression, allowing quantitative measurement of substrate recombination, are also being developed. In addition, we have initiated an evolutionary analysis of the function and structure of activation-induced deaminase, an essential molecule involved both in CSR and SHM, aiming to identify CSR specific-cofactor(s). Combining these approaches, we will be able to define the DNA repair pathways involved in CSR and SHM. The suggested project requires access to patients with various defects in the DNA repair pathways. Many of these diseases are exceedingly rare. However, through worldwide collaboration, we have obtained samples from a majority of the diagnosed patients. We are also refining the existing screening methods and developing novel methods, that will allow identification of additional patients both with recognized and new diseases caused by mutations in DNA repair pathways. Finally, we hope to be able to address the question whether illegitimate CSR events are associated with predisposition to lymphomagenesis in patients with immunodeficiency/DNA repair defect(s), by analyzing the CSR induced chromosomal breaks and translocations in these patients. A large-scale sequencing project is also planned to characterize the CSRnome in B-cell lymphoma samples.

Principal Investigator

Qiang Pan Hammarström (Dr.)

Host institution

KAROLINSKA INSTITUTET

Address

Nobels Vag 5
17177 Stockholm

Sweden

Activity type

Higher or Secondary Education Establishments

EU Contribution

€ 1 888 166

Principal Investigator

Qiang Pan Hammarström (Dr.)

Administrative Contact

Kim Von Schoultz (Mr.)

Beneficiaries (1)

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KAROLINSKA INSTITUTET

Sweden

EU Contribution

€ 1 888 166

Project information

Grant agreement ID: 242551

Status

Closed project

  • Start date

    1 December 2009

  • End date

    30 November 2014

Funded under:

FP7-IDEAS-ERC

  • Overall budget:

    € 1 888 166

  • EU contribution

    € 1 888 166

Hosted by:

KAROLINSKA INSTITUTET

Sweden