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Molecular interplay at DNA breaks

The integrity of the eukaryotic genome is maintained through processes collectively known as the DNA damage response (DDR). European researchers analysed the proteins that participate in the repair process in lymphocytes.
Molecular interplay at DNA breaks
The DDR surveillance mechanisms monitor chromosome status to ensure correct recombination and segregation, thereby prohibiting the transfer of mutations on to daughter cells. If left unrepaired, double strand DNA breaks (DSB) can lead to immunodeficiency, various developmental and neurological diseases as well as cancer. The histone protein components of chromatin assist in this response by creating a DNA region with damage-specific characteristics. Phosphorylation of H2AX is the most striking example of how a chromatin modification can promote genome stability.

Intriguingly, B lymphocytes have adapted the same repair pathways for generating antibody diversity through a DNA rearrangement reaction called immunoglobulin heavy-chain (IgH) class-switch recombination (CSR). If the induced DNA breaks are not properly resolved, this B cell-specific DNA damage can lead to the formation of oncogenic chromosomal translocations.

Scientists of the EU-funded DDR IN LYMPHOCYTES (Identifying functional proteins at DNA breaks with quantitative proteomics in primary lymphocytes) project wished to investigate the mechanism underlying the chromatin-associated suppression of genomic instability and cancer. Towards this goal, they analysed chromatin on a proteomic scale of irradiated lymphocytes from wild-type and H2AX-deficient mice.

They optimised a biochemical method called chromatin enrichment for proteomics (ChEP), which allowed them to map protein landscapes at DSBs with unprecedented resolution and accuracy. Scientists identified various novel chromatin-associated proteins and performed targeted genetic screening to validate their role in maintaining genome stability.

Overall, the findings of the DDR IN LYMPHOCYTES study underscored the role of chromatin in DDR and DSB repair in lymphocytes. They might also provide novel targets for the design of therapeutic strategies against cancer or immunodeficiency.

Related information


DNA damage response, H2AX, B lymphocytes, DDR IN LYMPHOCYTES, ChEP
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