DNA double-strand breaks (DSBs) signaling and repair is crucial to preserve genomic integrity and maintain cellular homeostasis. During the response to DSBs, histone ubiquitylation by RNF168 is a critical event, which or-chestrates the recruitment of downstream effectors, e.g. BRCA1 and 53BP1. While 53BP1 licenses the non-homologous end joining (NHEJ), BRCA1 initiates the DNA resection thus enabling homologous recombination (HR). Under conditions of ubiquitin starvation, mostly resulting from proteotoxic stress, the ubiquitin-dependent accumulation of DNA damage response proteins at the sites of DNA damage is impaired. Therefore, the proteo-toxic stress is commonly manifested by an attenuation of ubiquitin-mediated DSBs response. However, we have identified several cancer cell lines that display recruitment of 53BP1 to the sites of DSBs under the conditions of pro-teasome inhibitor (Bortezomib or MG132) induced proteo-toxic stress, i.e., under substantial depletion of nuclear free ubiquitin levels. This review brings a brief description of two major DSBs repair pathways: HR and NHEJ, their functional dependency on signaling through ubiquitin and a discussion of newly identified phenomenon of proteo-toxic stress resistant response to DNA double-strand breaks.

Ústav molekulárnej a translačnej medicíny Lekárska fakulta Univerzity Palackého v Olomouci Hněvotínská 5 779 00 Olomouc

Repair of double-strand breaks under condition of ubiquitin deficiency / proteotoxic stress

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