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26.10.15 Jackson group publish new screening technique for ubiquitin E2 enzymes involved in DNA repair pathways

last modified Jan 25, 2016 12:20 PM
Latest paper from the Gurdon Institute’s Jackson lab describes new methods for screening ubiquitin-mediated pathways in the DNA-damage response
26.10.15  Jackson group publish new screening technique for ubiquitin E2 enzymes involved in DNA repair pathways

Plot of effect on the DNA-damage response of small interfering RNAs (siRNAs) targeting different E2 enzymes

Systematic E2 screening reveals a UBE2D-RNF138-CtIP axis promoting DNA repair

Schmidt, CK et al. Nature Cell Biology (2015)

Advance online publication 26 October 2015

 

 

Recently, ubiquitylation has emerged as a key regulator of the DNA-damage response (DDR).  Mediated by two E1 activating, ~40 E2 conjugating and >600 E3 ligating enzymes, posttranslational modification by ubiquitin modulates the stability, localisation, activity or interaction properties of proteins.  However, few systematic analyses of human E2s or E3s have been conducted, although recent proteomic approaches have identified hundreds of DDR-regulated ubiquitylation substrates, suggesting that E2s and many E3s with DDR roles await discovery.

Steve Jackson’s group has developed a new screening technique to examine the human ubiquitin E2 enzymes to pinpoint those that play a role in repairing the most cytotoxic DNA lesion, the double-strand break. In this paper they present details of three proteins that form one specific pathway/axis to enable DNA repair by homologous recombination.

By following up one of the ‘hits’ in their three-module screen, they identify the downstream events from UBE2Ds-mediated ubiquitylation as involving the nuclear ligase RNF138 and CtIP (also known as RBBP8), which promotes DNA-end resection in the initial steps of repair by homologous recombination.

The researchers show that UBE2Ds and RNF138 accumulate at DNA damage sites (induced by laser micro-irradiation mimicking ionising radiation) and that these proteins act at early resection stages by promoting CtIP ubiquitylation and accrual.

This work supplies insights into regulation of double-strand break repair by homologous recombination. Moreover, it provides a rich information resource on E2s that can be exploited by follow-on studies.

 

More info on Jackson lab

Studying development to understand disease

The Gurdon Institute is funded by Wellcome and Cancer Research UK to study the biology of development, and how normal growth and maintenance go wrong in cancer and other diseases.

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Link to full list on PubMed