In cells of higher eukaryotes, repair of DNA double strand breaks (DSBs) 
utilizes different forms of potentially error-prone non-homologous end joining 
(NHEJ): canonical DNA-PK-dependent (C-NHEJ) and alternative backup pathways 
(A-NHEJ). In contrast to C-NHEJ, A-NHEJ shows pronounced efficiency fluctuations 
throughout the cell cycle and is severely compromised as cells cease 
proliferating and enter the plateau phase (Windhofer et al., 2007 [23]). The 
molecular mechanisms underpinning this response remain unknown but changes in 
chromatin structure are prime candidate-A-NHEJ-modulators. Since parameters 
beyond chromatin acetylation appear to determine A-NHEJ efficiency (Manova et 
al., 2012 [42,76]), we study here the role of chromatin decondensation mediated 
either by treatment with 5'-aza-2'-deoxycytidine (AzadC) or growth in hypotonic 
conditions, on A-NHEJ. We report that both treatments have no detectable effect 
on C-NHEJ but provoke, specifically for A-NHEJ, cell-growth-dependent effects. 
These results uncover for the first time a link between A-NHEJ and chromatin 
organization and provide means for understanding the regulatory mechanisms 
underpinning the growth-state dependency of A-NHEJ. A-NHEJ is implicated in the 
formation of chromosomal translocations and in chromosome fusions that underlie 
genomic instability and carcinogenesis. The observations reported here may 
therefore contribute to the development of drug-based A-NHEJ 
suppression-strategies aiming at optimizing cancer treatment outcomes and 
possibly also at suppressing carcinogenesis.