Institute for Biomedical Research Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42-44, 60596 Frankfurt, Germany
DNA damage repair:
It was shown by Guo et al. (2008) that AVEN, in addition to binding to the apoptotic machinery, is also able to bind one of the key players in DNA damage repair, the ataxia telangiectasia mutated (ATM) kinase. Overexpression of AVEN in Xenopus laevis egg extracts induced a cell cycle arrest at G2/M which is in large part ATM dependent, whereas the absence of AVEN impaired ATM-mediated checkpoint function. An intrinsic loop of activation exists between AVEN and ATM: AVEN binds to the kinase domain of ATM (appr. aa 2500-3000) and, in turn, is phosphorylated by ATM at S135 and S308. This phosphorylation seems to enhance AVENs activating influence on ATM. Esmaili et al. (2010) were able to demonstrate that AVEN possesses a nuclear export signal (NES) which is located between aa 282 and 293. Under normal physiological conditions, AVEN is shuttled outside of the nucleus by Exportin-1/CRM1 whereas inhibition of CRM1 by leptomycin or mutation of the AVEN NES leads to nuclear accumulation of the protein. The NES/nuclear-cytosolic shuttling of AVEN might be important for its cell cycle regulatory functions and its role in DNA damage repair.
Depending on the degree of DNA damage, AVEN is possibly a multifunctional protein, finetuning the cellular decisions of cell cycle arrest and apoptosis in the DNA damage response.
Inga Maria Melzer ; Martin Zörnig
AVEN (apoptosis, caspase activation inhibitor)
Atlas Genet Cytogenet Oncol Haematol. 2013-10-01
Online version: http://atlasgeneticsoncology.org/gene/43158/aven-(apoptosis-caspase-activation-inhibitor)