1513coordinated fashion through ATR-depend-ent phosphorylation.Almost all DNA-repair pathways processDNA damage through extensive RPA-ssDNA intermediates. Pathways such asbase excision repair (BER) that do not gen-erate significant RPA-ssDNA intermedi-ates appear invisible to the checkpoint sys-tem (7). Stalled replication forks areknown to expose extended regions of RPA-ssDNA (8). Thus, the ATR-dependentcheckpoint can respond to multiple DNAdamage and replication problems by recog-nizing RPA-ssDNA, a common topologicalintermediate. Importantly, this biochemicalunderstanding of damage detection willhelp lay to rest a myriad of misunderstoodobservations linking specific DNA-pro-cessing enzymes (such as helicases, nucle-ases, repair and replication proteins) tocheckpoint signaling. Any mutation influ-encing DNA metabolism can potentiallyinfluence the extent of RPA-ssDNA gener-ation. This will have a corresponding, butindirect, impact on the ATR-dependentcheckpoint pathway.Is RPA-ssDNA the sole activator of theATR-dependent checkpoint? Certainly, re-ports that Ddc2 (ATRIP) directly binds toDSBs (9) are not supported by Zou andElledge’s analysis. DSBs are the most dan-gerous initial lesion to a cell, and it is in-triguing that the parallel ATM-dependentcheckpoint pathway responds specificallyto DSBs. ATM-dependent signaling re-quires the recombination repair proteincomplex Mre11-Rad50-Xrs2 (MRX), andboth ATM and MRX associate with DSB-damaged chromatin. Does the ATM path-way respond directly to DSBs (before thegeneration of RPA-ssDNA) by directlybinding to DSB-MRX complexes, or isthere also a requirement for RPA-ssDNAfor ATM activation? Possibly, MRX fulfillsan ATRIP-like function for ATM, allowingit to respond specifically to RPA-ssDNAgenerated by the MRX-dependent nucleas-es. Recent data suggesting that ATM is ac-tivated by chromatin distortions, independ-ently of DNA breaks (10), do not exclude arole for RPA-ssDNA because chromatindistortion may expose ssDNA.Zou and Elledge demonstrate that asimple paradigm for DNA-damage signal-ing is conserved from bacteria to humans.Prokaryotes sense RecA-ssDNA, whereaseukaryotes sense RPA-ssDNA. Detectingmultiple DNA perturbations, particularlythose caused by replication stress, is vitalto coordinate DNA repair with cell cycleprogression and apoptosis. Such coordina-tion is essential for survival of cells andthe whole organism. That ssDNA under-lies damage detection shows that, in theend, the beginning of signaling has a sim-ple explanation.References1. L. Zou, S. J. Elledge,Science300, 1542 (2003).2. K. Sugasawaet al.,Genes Dev.15, 507 (2001).3. D. Lydall, T.Weinert,Science270, 1488 (1995).4. S. E. Leeet al.,Cell94, 399 (1998).5. V. Costanzoet al.,Mol. Cell11, 203 (2003).6. J.A. Melo, J. Cohen, D. P.Toczyski,Genes Dev.15, 2809(2001).7. C. Leroy, C. Mann, M. C. Marsolier,EMBO J.20, 2896(2001).8. J. M. Sogo, M. Lopes, M. Foiani,Science279, 599(2002).9. J. Rouse, S. P. Jackson,Mol. Cell9, 857 (2002).10. C. J. Bakkenist, M. B. Kastan,Nature421, 499 (2003).Recent reports (1–4) on the tungsten(W) isotope composition of mete-orites have led to a completely re-vised time scale for the formation of theterrestrial planets. The results show thatmost of planet Earth had formed within~10 million years (1, 2) after the formationof the solar system some 4567 millionyears ago (when the first solid grainsformed in the solar nebula) (5). The Moon-forming event happened ~30 million yearsafter solar system formation, when Earthwas fully grown (2, 3).The decay of the hafnium isotope 182Hf(with a half-life of 9 million years) into182W is the best “clock” we have for tracingthe formation of terrestrial planets duringthe first 50 million years of solar systemhistory. The behavior of these elementsduring metal-silicate separation, which oc-curs during the formation of planetarycores, is well understood.Hafnium is a lithophile element (it has astrong affinity for silicate liquid) and staysentirely in the silicate mantle (and crust) ofthe planet. Hence, the mantle is where ra-dioactive decay of 182Hf to 182W occurs. Incontrast, tungsten is siderophilic (it has astrong affinity for iron melt), and about 90to 95% of it is partitioned into the metalwhen metal and silicate separate in the core-forming process. After 50 million years, theHf-W chronometer is a dead clock becausealmost all 182Hf has decayed, but for the first50 million years of solar system history, it isideal for tracking a planet’s growth.In the earliest work on this chronometer(6, 7), we found that the solar system’s initial182W/183W value was about 3 to 4 parts in10,000 lower than the present terrestrial val-ue, and inferred a relatively short time scalefor the formation of Earth. This short timescale was challenged by Lee and Halliday(8), who reported that Earth and chondriticmeteorites have essentially identical 182W/183Wvalues to within 20 parts per million—indi-cating that Earth formed relatively late, afterthe decay of 182Hf (when the Hf-W clockwas dead). They reported an age of core for-mation within Earth corresponding to 60 ±10 million years after solar system forma-tion. This age has been widely cited.However, because theclock was dead by thistime, it should havebeen reported as anytime between 50 mil-lion years after solarsystem formation andthe present. Last year, threegroups reported that182W/183W in chon-drites is lower thanthat of Earth by 2parts in 10,000, andthus intermediate be-tween the initial solarvalue and that of Earthtoday (1–4). Thesenew results have fun-damentally changedthe way in which theGEOCHEMISTRYHow Old Is Planet Earth?Stein B. JacobsenGiant impactGasanddustTime (millions of years)EmbryosEarth010300.1EarthMoonTThhee ffoorrmmaattiioonn ooff EEaarrtthh.The first new solid grains formed from the gasand dust cloud called the Solar Nebula some 4567 million years ago.Within 100,000 years, the first embryos of the terrestrial planets hadformed. Some grew more rapidly than others, and within 10 millionyears, ~64% of Earth had formed; by that time, proto-Earth must havebeen the dominant planet at 1 astronomical unit (the distance be-tween Earth and the Sun). Accretion was effectively complete at 30million years, when a Mars-sized impactor led to the formation of theMoon. The figure is not to scale.The author is in the Department of Earth andPlanetary Sciences, Harvard University, Cambridge,MA 02138, USA. E-mail: [email protected]
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