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The DNA-damage response in human biology and disease
TLDR
The authors' improving understanding of DNA-damage responses is providing new avenues for disease management, and these responses are biologically significant because they prevent diverse human diseases. Expand
Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy
TLDR
BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis, illustrating how different pathways cooperate to repair damage. Expand
Identification and Characterization of a Novel and Specific Inhibitor of the Ataxia-Telangiectasia Mutated Kinase ATM
TLDR
KU-55933 is a novel, specific, and potent inhibitor of the ATM kinase, which did not potentiate the cytotoxic effects of ionizing radiation on ataxia-telangiectasia cells, nor did it affect their cell cycle profile after DNA damage. Expand
Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage
TLDR
Findings reveal that recruitment of these PIKKs to DNA lesions occurs by common mechanisms through an evolutionarily conserved motif, and provide direct evidence that PIKK recruitment is required for PIKK-dependent DNA-damage signalling. Expand
Human CtIP promotes DNA end resection
TLDR
These findings establish evolutionarily conserved roles for CtIP-like proteins in controlling DSB resection, checkpoint signalling and homologous recombination. Expand
ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks
TLDR
It is shown that ATM and the nuclease activity of meiotic recombination 11 are required for the processing of DNA double-strand breaks (DSBs) to generate the replication protein A (RPA)-coated ssDNA that is needed for ATR recruitment and the subsequent phosphorylation and activation of Chk1. Expand
MDC1 Directly Binds Phosphorylated Histone H2AX to Regulate Cellular Responses to DNA Double-Strand Breaks
TLDR
It is shown that MDC1/NFBD1-gammaH2AX complex formation regulates H2AX phosphorylation and is required for normal radioresistance and efficient accumulation of DNA-damage-response proteins on damaged chromatin. Expand
Orchestration of the DNA-Damage Response by the RNF8 Ubiquitin Ligase
TLDR
The results demonstrate how the DNA-damage response is orchestrated by ATM-dependent phosphorylation of MDC1 and RNF8-mediated ubiquitination and promote the G2/M DNA damage checkpoint and resistance to ionizing radiation. Expand
DNA double-strand breaks: signaling, repair and the cancer connection
TLDR
Recent progress is described in understanding of how cells detect and signal the presence and repair of one particularly important form of DNA damage induced by ionizing radiation—the DNA double-strand break (DSB). Expand
A DNA damage checkpoint response in telomere-initiated senescence
TLDR
It is proposed that telomere-initiated senescence reflects a DNA damage checkpoint response that is activated with a direct contribution from dysfunctional telomeres. Expand
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