Autori: G Balmus, PX Lim, A Oswald, KR Hume, A Cassano, J Pierre, A Hill, W Huang, A August, T Stokol, T Southard, RS Weiss
Editorial: Oncogene, 2015.
Cells are under constant attack from genotoxins and rely on a multifaceted DNA damage response (DDR) network to maintain
genomic integrity. Central to the DDR are the ATM and ATR kinases, which respond primarily to double-strand DNA breaks (DSBs)
and replication stress, respectively. Optimal ATR signaling requires the RAD9A-RAD1-HUS1 (9-1-1) complex, a toroidal clamp that is
loaded at damage sites and scaffolds signaling and repair factors. Whereas complete ATR pathway inactivation causes embryonic
lethality, partial Hus1 impairment has been accomplished in adult mice using hypomorphic (Hus1neo) and null (Hus1Δ1
) Hus1 alleles,
and here we use this system to define the tissue- and cell type-specific actions of the HUS1-mediated DDR in vivo. Hus1neo/Δ1 mice
showed hypersensitivity to agents that cause replication stress, including the crosslinking agent mitomycin C (MMC) and the
replication inhibitor hydroxyurea, but not the DSB inducer ionizing radiation. Analysis of tissue morphology, genomic instability, cell
proliferation and apoptosis revealed that MMC treatment caused severe damage in highly replicating tissues of mice with partial
Hus1 inactivation. The role of the 9-1-1 complex in responding to MMC was partially ATR-independent, as a HUS1 mutant that was
proficient for ATR-induced checkpoint kinase 1 phosphorylation nevertheless conferred MMC hypersensitivity. To assess the
interplay between the ATM and ATR pathways in responding to replication stress in vivo, we used Hus1/Atm double mutant mice.
Whereas Hus1neo/neo and Atm−/− single mutant mice survived low-dose MMC similar to wild-type controls, Hus1neo/neoAtm−/− double
mutants showed striking MMC hypersensitivity, consistent with a model in which MMC exposure in the context of Hus1 dysfunction
results in DSBs to which the ATM pathway normally responds. This improved understanding of the inter-dependency between two
major DDR mechanisms during the response to a conventional chemotherapeutic illustrates how inhibition of checkpoint factors
such as HUS1 may be effective for the treatment of ATM-deficient and other cancers.
Cuvinte cheie: cancer, HUS1, ATM, MMC, ATR