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• W2026538544 abstract "In this issue of Molecular Cell, Barlow et al., 2008Barlow J.H. Lisby M. Rothstein R. Mol. Cell. 2008; 30 (this issue): 73-85Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar show that not all DNA double-strand breaks are processed equally and that the chemical nature of DNA ends guides different paths to DNA repair. In this issue of Molecular Cell, Barlow et al., 2008Barlow J.H. Lisby M. Rothstein R. Mol. Cell. 2008; 30 (this issue): 73-85Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar show that not all DNA double-strand breaks are processed equally and that the chemical nature of DNA ends guides different paths to DNA repair. DNA derives its genetic information content from the specific sequential arrangement of its four basic building blocks in a long linear double-stranded polymer. Breaks in the polymer are therefore potentially dramatic challenges to cells. To maintain the integrity of genetic information, cells have evolved multiple responses to cope with DNA double-strand breaks (DSBs), including cell-cycle checkpoint responses and two mechanistically distinct DSB repair mechanisms: nonhomologous DNA end-joining and homologous recombination. The existence of distinct DSB repair mechanisms spawns the question of what determines which mechanisms will act on a DNA end. Is there a direct competition for broken ends between different DSB repair mechanisms? Or, because not all DSBs are created equal, is it the chemical structure of the DNA ends and/or the circumstances under which the DSB is generated that influence its path to repair (Wyman and Kanaar, 2006Wyman C. Kanaar R. Annu. Rev. Genet. 2006; 40: 363-383Crossref PubMed Scopus (570) Google Scholar)? In this issue of Molecular Cell, Barlow et al., 2008Barlow J.H. Lisby M. Rothstein R. Mol. Cell. 2008; 30 (this issue): 73-85Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar provide experimental evidence for the latter idea by demonstrating differential mechanistic responses to DSBs produced by ionizing radiation and endonuclease cleavage. The two most common methods to experimentally induce DSBs are cellular exposure to ionizing radiation or endonuclease expression (Wyman and Kanaar, 2006Wyman C. Kanaar R. Annu. Rev. Genet. 2006; 40: 363-383Crossref PubMed Scopus (570) Google Scholar). Although both treatments break DNA directly, they result in very different chemical structures at the severed end. Care should be taken in generalizing results obtained by these different methods for mechanisms of DSB repair because the specific chemical structure at the end can demand specific cellular components for repair. Enzymatic cleavage usually produces chemically defined or “clean” DNA ends, often with a terminal 5′-phosphate and 3′-hydroxyl. Many enzymes that restore DNA chain continuity, notably ligases and polymerases, require a 5′-phosphate or a 3′-hydroxyl end as a substrate. Thus, nuclease-generated ends are proper substrates for some types of DNA repair without further processing. Consistent with previous observations (Ira et al., 2004Ira G. Pellicioli A. Balijja A. Wang X. Fiorani S. Carotenuto W. Liberi G. Bressan D. Wan L. Hollingsworth N.M. et al.Nature. 2004; 431: 1011-1017Crossref PubMed Scopus (549) Google Scholar), Barlow et al., 2008Barlow J.H. Lisby M. Rothstein R. Mol. Cell. 2008; 30 (this issue): 73-85Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar show that nuclease-generated ends are not resected during the G1 phase of the cell cycle in the yeast Saccharomyces cerevisiae. However, the observation that RPA, a single-strand DNA-binding protein, accumulates in nuclear foci induced by ionizing radiation indicates that resulting DNA ends are resected in G1. As pointed out by Barlow et al., 2008Barlow J.H. Lisby M. Rothstein R. Mol. Cell. 2008; 30 (this issue): 73-85Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar, ionizing radiation can sever the DNA backbone in several ways, leaving a variety of chemical structures sometimes referred to as “dirty” breaks or “frayed” ends. As clean termini must be exposed for eventual repair to occur, some resection is always required at dirty ends. But how are the nuclease breaks spared from resection, and how are dirty ends resected? The answer to the first question appears to lie in a structure-specific DNA-binding protein, Ku70/80. This heterodimeric protein has affinity for DNA ends, and in Ku-deficient cells, nuclease-generated breaks also induce RPA foci, indicating resection of these ends as well. Perhaps dirty ends do not bind Ku, or Ku is not stabilized at such ends. Indeed, the structure of DNA-bound Ku shows the protein to be a ring that fits very tightly around a B form double-stranded DNA end. The DNA termini created by ionizing radiation might not fit into this ring, or they might be preferentially bound by another protein complex with increased affinity for DNA ends, for instance the Mre11 complex, which also has nuclease activity. It will be interesting to determine if any of the DNA termini produced by ionizing radiation have a decreased affinity for binding Ku or increased affinity for other proteins required early in DSB repair. How broken DNA ends are resected in G1 remains an intrigue. The Mre11 complex is almost certainly involved, as it cohabitates with RPA in ionizing radiation-induced nuclear foci, although cells expressing a nuclease-defective mre11 allele only show a slight delay in RPA focus formation (Barlow et al., 2008Barlow J.H. Lisby M. Rothstein R. Mol. Cell. 2008; 30 (this issue): 73-85Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar). Recently, Sae2 was shown to have nuclease activity, and, specifically in conjunction with the Mre11 complex, it influences cleavage of DNA secondary structures (Lengsfeld et al., 2007Lengsfeld B.M. Rattray A.J. Bhaskara V. Ghirlando R. Paull T.T. Mol. Cell. 2007; 28: 638-651Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar). However, again cells deleted for SAE2 are only slightly delayed in ionizing radiation-induced RPA focus formation. Similarly, in mammalian cells, some ionizing radiation-induced DNA ends, presumably those with chemical bonds broken in the base or sugar groups, need processing by the Artemis nuclease in G1 (Riballo et al., 2004Riballo E. Kuhne M. Rief N. Doherty A. Smith G.C. Recio M.J. Reis C. Dahm K. Fricke A. Krempler A. et al.Mol. Cell. 2004; 16: 715-724Abstract Full Text Full Text PDF PubMed Scopus (679) Google Scholar). Supporting the idea that different damaged DNA structures require different means of resection, nucleases, including Exo1, Mre11, and Pso2, have distinct roles in processing DNA damage resulting from different agents in S. cerevisiae (Lam et al., 2008Lam A.F. Krogh B.O. Symington L.S. DNA Repair (Amst.). 2008; 7 (Published online March 4, 2008): 655-662https://doi.org/10.1016/j.dnarep.2007.12.014Crossref PubMed Scopus (13) Google Scholar). In contrast to G1, when processed breaks must be repaired by nonhomologous DNA end-joining, more extensive DNA end resection occurs in S/G2, presumably to facilitate the strand invasion steps of homologous recombination repair favored in these cell-cycle stages. In Schizosaccharomyces pombe and mammalian cells, this resection might be controlled by the cell-cycle-dependent regulation of the Sae2 orthologs Ctp1 and CtIP, respectively (Limbo et al., 2007Limbo O. Chahwan C. Yamada Y. de Bruin R.A. Wittenberg C. Russell P. Mol. Cell. 2007; 28: 134-146Abstract Full Text Full Text PDF PubMed Scopus (251) Google Scholar, Sartori et al., 2007Sartori A.A. Lukas C. Coates J. Mistrik M. Fu S. Bartek J. Baer R. Lukas J. Jackson S.P. Nature. 2007; 450: 509-514Crossref PubMed Scopus (918) Google Scholar). The steps described above indicate how repairable DNA structures are generated, but these DNA structures alone are not sufficient to trigger a checkpoint response. Instead, a nucleoprotein structure is required in which the single-strand DNA is bound by RPA and the single-strand/double-strand junction by the Ddc1-Rad17-Mec3 (abbreviated as 9-1-1 below for its designation in human cells; RAD9-RAD1-HUS1) checkpoint clamp (Majka et al., 2006Majka J. Niedziela-Majka A. Burgers P.M. Mol. Cell. 2006; 24: 891-901Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar). It is this nucleoprotein structure that sets the stage for checkpoint activation by triggering Mec1 (ATR in mammalian cells) kinase activity. Following the formation of individual foci, presumably at DSB sites, Barlow et al., 2008Barlow J.H. Lisby M. Rothstein R. Mol. Cell. 2008; 30 (this issue): 73-85Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar show that Ddc2 (the ATR-interacting protein ATRIP in mammalian cells) accumulation in G1 phase S. cerevisiae cells depends on 9-1-1. In asynchronous mammalian cells and S/G2 S. cerevisiae cells, ATR/ATRIP recruitment is independent of the chromatin-bound 9-1-1 complex (Barlow et al., 2008Barlow J.H. Lisby M. Rothstein R. Mol. Cell. 2008; 30 (this issue): 73-85Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar, Zou et al., 2002Zou L. Cortez D. Elledge S.J. Genes Dev. 2002; 16: 198-208Crossref PubMed Scopus (421) Google Scholar). The same activating structure could still be responsible but formed with the PCNA DNA polymerase processivity clamp in S/G2 phase cells. Creating and maintaining the structure to activate cell-cycle checkpoints is likely similar at sites of UV-light-induced damage, as the same proteins are involved: 9-1-1, ATR/ATRIP, Rad17-RFC, and Chk1. UV-light-induced DNA damage is also processed by nucleases that expose single-stranded DNA gaps with a single-strand/double-strand junction. Subsequent association of RPA and a clamp completes the specific nucleoprotein structure independent of the distal DNA having an end or not. Cell-cycle checkpoint signaling is important to ensure that cells do not go through S phase and into mitosis with damaged DNA. Thus, in the absence of effective repair, checkpoint proteins must be maintained in an activated state. Barlow et al., 2008Barlow J.H. Lisby M. Rothstein R. Mol. Cell. 2008; 30 (this issue): 73-85Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar show that maintaining Ddc2 at DNA damage-induced foci in S/G2 cells is influenced by RPA modifications of a yet-unidentified nature. This observation implies that dynamic aspects of protein accumulation into damage-induced foci are critical for biological outcome. Experiments that report on the dynamic behavior of checkpoint proteins in live cells can now provide vital information on this aspect of the DNA damage response. An interesting picture is developing from the cellular work of Barlow et al., 2008Barlow J.H. Lisby M. Rothstein R. Mol. Cell. 2008; 30 (this issue): 73-85Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar and the biochemical characterization of the nucleoprotein structure required for checkpoint activation (Majka et al., 2006Majka J. Niedziela-Majka A. Burgers P.M. Mol. Cell. 2006; 24: 891-901Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar). The DNA substrate itself mediates the early response to DSBs as its nature determines which nuclease(s), if any, will be able to act on it. By contrast, the subsequent cell-cycle checkpoint response is not triggered by DNA structure directly, nor by RPA-bound single-stranded DNA. This regulation makes biological sense, as these entities are common intermediates in normal DNA metabolism. Rather, kinase activity required for establishing the checkpoint is triggered only when the 9-1-1 complex is loaded through the action of Rad17/RFC on RPA-coated DNA at the 5′ end of a single-strand/double-strand junction. Conceptually, this process makes controlling DNA damage checkpoint activation similar to other DNA transactions, including the initiation of DNA replication and transcription, that also obtain their required high specificity through the build up of specialized nucleoprotein structures (Echols, 1986Echols H. Science. 1986; 233: 1050-1056Crossref PubMed Scopus (205) Google Scholar). Differential Regulation of the Cellular Response to DNA Double-Strand Breaks in G1Barlow et al.Molecular CellApril 11, 2008In BriefDouble-strand breaks (DSBs) are potentially lethal DNA lesions that can be repaired by either homologous recombination (HR) or nonhomologous end-joining (NHEJ). We show that DSBs induced by ionizing radiation (IR) are efficiently processed for HR and bound by Rfa1 during G1, while endonuclease-induced breaks are recognized by Rfa1 only after the cell enters S phase. This difference is dependent on the DNA end-binding Yku70/Yku80 complex. Cell-cycle regulation is also observed in the DNA damage checkpoint response. Full-Text PDF Open Archive" @default.
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• W2026538544 title "From DNA End Chemistry to Cell-Cycle Response: The Importance of Structure, Even When It's Broken" @default.
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