During the evolution of cancer, the incipient tumour experiences 'oncogenic stress', which evokes a counter-response to eliminate such hazardous cells. However, the nature of this stress remains elusive, as does the inducible anti-cancer barrier that elicits growth arrest or cell death. Here we show that in clinical specimens from different stages of human tumours of the urinary bladder, breast, lung and colon, the early precursor lesions (but not normal tissues) commonly express markers of an activated DNA damage response. These include phosphorylated kinases ATM and Chk2, and phosphorylated histone H2AX and p53. Similar checkpoint responses were induced in cultured cells upon expression of different oncogenes that deregulate DNA replication. Together with genetic analyses, including a genome-wide assessment of allelic imbalances, our data indicate that early in tumorigenesis (before genomic instability and malignant conversion), human cells activate an ATR/ATM-regulated DNA damage response network that delays or prevents cancer. Mutations compromising this checkpoint, including defects in the ATM-Chk2-p53 pathway, might allow cell proliferation, survival, increased genomic instability and tumour progression.

SummaryALC1, a novel PARP1-stimulated chromatin-remodelling enzyme promotes DNA repair.Post-translational modifications play key roles in orchestrating chromatin plasticity. Although various chromatin-remodelling enzymes have been described that respond to specific histone modifications, little is known about the role of poly(ADP-ribose) in chromatin remodelling. Here, we identify a novel chromatin-remodelling enzyme, ALC1 (Amplified in Liver Cancer 1), that is specifically regulated by poly(ADP-ribosyl) ation. ALC1 binds poly(ADP-ribose) via a C-terminal Macro domain and catalyzes PARP1-stimulated nucleosome sliding, conferred by an N-terminal ISWI-related helicase core. Our results define ALC1 as a novel DNA damage-response protein, whose role in this process is sustained by its association with known DNA repair factors and its rapid poly(ADP-ribose)-dependent recruitment to DNA damage sites. Furthermore, we show that depletion or overexpression of ALC1 results in sensitivity to DNA-damaging agents. Collectively, these results provide new insights into the mechanisms by which poly(ADP-ribose) regulates DNA repair.The restricted accessibility of DNA within chromatin presents a barrier to DNA manipulations that require direct protein-DNA interactions (1-3). Processes such as transcription, repair and replication that require efficient DNA recognition are therefore dependent on the appropriate modulation of chromatin structure. Chromatin relaxation is a critical event that occurs during DNA repair and is associated with post-translational poly(ADP-ribose) (PAR) modification (4). PAR is synthesized in a reaction that utilizes NAD+ as a substrate by the PARP family of enzymes, of which PARP1 (and to a lesser extent PARP2) respond to DNA strand breaks (5-7). As a consequence of poly(ADP-

Fanconi anemia (FA) is a complex cancer susceptibility disorder associated with DNA repair defects and infertility, yet the precise function of the FA proteins in genome maintenance remains unclear. Here we report that C. elegans FANCD2 (fcd-2) is dispensable for normal meiotic recombination but is required in crossover defective mutants to prevent illegitimate repair of meiotic breaks by nonhomologous end joining (NHEJ). In mitotic cells, we show that DNA repair defects of C. elegans fcd-2 mutants and FA-deficient human cells are significantly suppressed by eliminating NHEJ. Moreover, NHEJ factors are inappropriately recruited to sites of replication stress in the absence of FANCD2. Our findings are consistent with the interpretation that FA results from the promiscuous action of NHEJ during DNA repair. We propose that a critical function of the FA pathway is to channel lesions into accurate, as opposed to error-prone, repair pathways.