端粒的DNA复制过程有两个检验点(图).pdfVIP

The DNA Damage Machinery and Homologous Recombination Pathway Act Consecutively to Protect Human Telomeres Ramiro E. Verdun1 and Jan Karlseder1,* 1The Salk Institute for Biological Studies, 10010 North Torrey Pines Rd., La Jolla, CA 92037, USA *Contact: karlseder@ DOI 10.1016/j.cell.2006.09.034 SUMMARY complex (MRE11-NBS1-RAD50) is one of the first com- plexes to be recruited to the lesion (Carson et al., 2003; Telomeres protect chromosome ends from be- Lewis et al., 2004). This is followed by activation of Phos- ing detected as lesions and from triggering DNA phatidyl-Inositol 3 Kinase-like protein Kinase (PIKK) family damage checkpoints. Paradoxically, telomere members ATM and the RAD3-related ATR kinase by the function depends on checkpoint proteins such MRN complex (Carson et al., 2003; Jazayeri et al., 2006). as ATM and ATR, but a molecular model ex- Activation of these kinases triggers signals that will halt plaining this seemingly contradictory relation- the cell cycle to permit DNA repair. While a stalled replica- tion fork exposes long tracks of single-stranded DNA ship has been missing so far. Here we show 0 (ssDNA), a DSB has to be processed to yield 3 single- that the DNA damage machinery acts on telo- stranded overhangs. In both cases, the exposed ssDNA meres in at least two independent steps. First, will be coated by Replication Protein A (RPA), which pro- the ATR-dependent machinery is r