Forschungs- & Entwicklungsinformationsdienst der Gemeinschaft - CORDIS


ATMINDDR Berichtzusammenfassung

Project ID: 281661
Gefördert unter: FP7-IDEAS-ERC
Land: United Kingdom

Final Report Summary - ATMINDDR (ATMINistrating ATM signalling: exploring the significance of ATM regulation by ATMIN)

We have made several notable discoveries relating to the discovery of novel ATM signalling pathway components and the molecular basis for ATM pathway selectivity.
Our previous work has shown that ATM signalling is mediated by 2 distinct pathways, the MRN-dependent pathway, and the ATMIN-dependent pathway. We demonstrated that components of the 2 pathways compete for ATM binding, and that this underlies pathway choice (Zhang et al. 2012). Further, we identified an important mechanism that influences this choice: we found that the E3 ubiquitin ligase UBR5 ubiquitylates ATMIN, and that ubiquitylated ATMIN has a lower affinity for ATM. Importantly, signals that activate MRN-dependent ATM signalling, such as double-strand breaks, increased the activity of UBR5 towards ATMIN. Therefore, the competition of MRN and ATMIN for ATM is controlled by signal-specific regulation of the relative affinity of the ATMIN cofactor (Zhang et al. 2014). In addition, we identified RAD18 and WRNIP1 as ATMIN interacting proteins responsible for activation of ATM signalling in response to replication stress (Kanu et al., 2016), and we also completed a study that described DMAP1 as a novel epigenetic regulator of ATM signalling (Penicud et al., 2014).
We also shed light on the function of ATMIN and ATM in hematopoietic stem cells, where ATMIN-dependent ATM signalling antagonised stem cell ageing (Anjos-Afonso et al., 2016). Importantly, we demonstrated a pro-tumorigenic function of ATMIN-dependent ATM signalling in glioblastoma multiforme, the most aggressive brain tumour (Blake et al., 2016), suggesting a new therapeutic strategy.

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United Kingdom
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