DNA damage and repair articles within Nature

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  • Letter |

    Although loss of XLF, a classical non-homologous DNA end-joining (NHEJ) repair factor, shows strong effects in non-lymphoid cells, in lymphoid cells its absence has only modest effects on V(D)J recombination. This study now shows that in lymphoid cells, two other repair factors — ATM kinase and histone protein H2AX — have functional redundancy with XLF. Thus, mice deficient in both ATM and XLF have compromised conventional NHEJ, although alternative end-joining is retained. The results hint that the redundant function in end-joining that XLF has with both ATM and H2AX may have to do with an ATM role in chromatin accessibility.

    • Shan Zha
    • , Chunguang Guo
    •  & Frederick W. Alt

  • Letter |

    Antigen receptor loci contain numerous gene segments that are recombined in response to antigen stimulation. The RAG endonuclease makes the double-strand breaks that initiate recombination. The ends of these breaks are hairpins that can only be cleaved by the Artemis nuclease. Here, it is shown that the specificity for Artemis is dictated by the histone protein H2AX, in cooperation with the repair protein MDC-1. In the absence of H2AX, another nuclease, CtIP, can open the ends but they are not joined efficiently; this leads to genomic instability.

    • Beth A. Helmink
    • , Anthony T. Tubbs
    •  & Barry P. Sleckman

  • Letter |

    Here it is shown that reactivation of endogenous telomerase activity in mice extends telomeres, reduces DNA damage signalling, allows resumption of proliferation in quiescent cultures, and eliminates degenerative phenotypes across multiple organs including testes, spleens and intestines. Accumulating evidence implicating telomere damage as a driver of age-associated organ decline and disease and the reversal of damage observed here support the development of regenerative strategies designed to restore telomere integrity.

    • Mariela Jaskelioff
    • , Florian L. Muller
    •  & Ronald A. DePinho

  • News & Views |

    Purification of the human tumour-suppressor protein BRCA2, which is crucial for DNA repair, has been a formidable challenge owing to its large size. That mission is now accomplished, providing biochemical insight. See Article p.678

    • Lee Zou

  • Article |

    DNA bases that are alkylated or deaminated are removed by DNA glycosylase repair enzymes. In structures of several other DNA glycosylases, the modified base inserts into the active site. These authors solve the structure of glycosylase AlkD, find that the modified base is extruded in an extrahelical position and propose a model for how this solvent-exposed position allows cleavage of N3- and N7-alkylated bases specifically.

    • Emily H. Rubinson
    • , A. S. Prakasha Gowda
    •  & Brandt F. Eichman

  • Letter |

    Two classes of enzyme — cyclin-dependent kinases (CDK) and Dbf4-dependent kinase (DDK) — facilitate the initiation of DNA replication in eukaryotes. It is now shown that, when DNA damage is sensed, another kinase, Rad53, halts the firing of late replication origins by inhibiting both the CDK and the DDK pathways. Rad53 acts on DDK directly by inhibiting Dbf4, whereas the CDK pathway is blocked by Rad53-mediated phosphorylation of the downstream CDK substrate Sld3.

    • Jaime Lopez-Mosqueda
    • , Nancy L. Maas
    •  & David P. Toczyski

  • Letter |

    The ends of chromosomes, known as telomeres, look like ends generated by double-strand breaks, but if treated as such the DNA damage repair system would initiate a checkpoint response and cause telomere–telomere fusions. These authors show that telomeres lack two types of histone modification that are required for recruitment of Crb2b53BP1, without which the checkpoint cannot be activated even if other DNA damage response proteins are recruited to a Taz1-deficient telomere.

    • Tiago Carneiro
    • , Lyne Khair
    •  & Miguel Godinho Ferreira

  • Letter |

    Cell cycle checkpoints, such as the S-phase checkpoint, delay cell division to give the cell time to repair any damaged DNA. Here it is shown that the MLL gene — frequently disrupted in leukaemia — is part of the S-phase checkpoint. When DNA is damaged, MLL is phosphorylated by the ATR protein, causing MLL to accumulate on chromatin and methylate histone H3 on lysine 4. This delays DNA replication. MLL translocations, such as those that occur in leukaemia, disrupt this pathway and cause genomic instability.

    • Han Liu
    • , Shugaku Takeda
    •  & James J.-D. Hsieh

  • Letter |

    When double-strand breaks occur in DNA, the broken ends must undergo processing to prepare them for repair. Here, and in an accompanying study, this processing reaction has now been replicated in vitro using yeast proteins. Processing minimally requires the activities of a helicase, a nuclease and a single-strand-binding protein, although the reaction is enhanced by the addition of three factors that help to target the core complex and stimulate the unwinding activity.

    • Hengyao Niu
    • , Woo-Hyun Chung
    •  & Patrick Sung

  • Letter |

    When double-strand breaks occur in DNA, the broken ends must undergo processing to prepare them for repair. Here, and in an accompanying study, this processing reaction has now been replicated in vitro using yeast proteins. Processing minimally requires the activities of a helicase, a nuclease and a single-strand-binding protein, although the reaction is enhanced by the addition of three factors that help to target the core complex and stimulate the unwinding activity.

    • Petr Cejka
    • , Elda Cannavo
    •  & Stephen C. Kowalczykowski

  • Article |

    The two hereditary breast cancer susceptibility genes, BRCA1 and BRCA2, have roles in responding to DNA damage. When they are mutated or absent, genomic instability, a contributory factor to cancer development, results. Studies of BRCA2 have been hampered by its large size, which makes purification of the full-length protein challenging. These authors report the first in vitro characterization of full-length BRCA2 and delineate the different ways by which BRCA2 facilitates RAD51-mediated homologous recombination.

    • Ryan B. Jensen
    • , Aura Carreira
    •  & Stephen C. Kowalczykowski

  • Article |

    When double-strand breaks occur in eukaryotic DNA, the chromatin that protects and organizes the genome must be removed from the vicinity of the break to allow repair factors to bind. Such chromatin displacement involves the addition of ubiquitin groups to histone proteins near the break by the ubiquitin ligases RNF8 and RNF168. Here it is shown that the enzyme OTUB1 prevents RNF168-dependent poly-ubiquitination. Pharmacological targeting of this process might enhance the DNA damage response.

    • Shinichiro Nakada
    • , Ikue Tai
    •  & Daniel Durocher

  • News & Views |

    The protein OTUB1 inhibits DNA repair without using its enzymatic activity. Instead, it sequesters a protein that is required for the assembly of certain forms of ubiquitin chain, which function as key signals during repair.

    • April Rose
    •  & Christian Schlieker

  • Letter |

    The repair enzyme (6–4) photolyase uses light energy to cleave the ultraviolet-induced bond between pyrimidine dimers. These authors use ultrafast spectroscopy to examine the detailed electron and proton movements during the catalytic photocycle. Histidine 364 is identified as the crucial residue involved in the rate-limiting step.

    • Jiang Li
    • , Zheyun Liu
    •  & Dongping Zhong

  • Letter |

    Normally, expression of bacterial DNA damage repair genes is repressed by the binding of LexA protein to SOS ‘boxes’ in their operators. DNA damage activates the RecA protein, which promotes autocleavage of LexA such that its repression is relieved and repair proteins are expressed. These authors solve several structures of LexA dimer bound to SOS box DNA, and find that the orientation of the DNA-binding wings can account for the strict intersite spacing.

    • Adrianna P. P. Zhang
    • , Ying Z. Pigli
    •  & Phoebe A. Rice

  • Letter |

    The rat is a animal model widely used for studying human physiology and disease, but functional genomics and genetic research have been stifled by the limited availability of gene targeting tools. These authors have established gene targeting by homologous recombination in rat embryonic stem cells, and have generated p53 gene knockout rats for the first time.

    • Chang Tong
    • , Ping Li
    •  & Qi-Long Ying

  • News & Views |

    Ultraviolet radiation can cause cancer through DNA damage — specifically, by linking adjacent thymine bases. Crystal structures show how the enzyme DNA polymerase η accurately bypasses such lesions, offering protection.

    • Suse Broyde
    •  & Dinshaw J. Patel

  • News & Views |

    Many decisions affect the fate of damaged DNA — for example, how to repair the damage, or whether to repair it at all and instead let the damaged cell die. An intricate web of molecular interactions affects such decisions.

    • Simon J. Boulton

  • Letter |

    Post-replicative repair (PRR) enables cells to bypass or overcome DNA damage during DNA replication. In eukaryotes, ubiquitylation of the replication clamp PCNA by components of the RAD6 pathway activates damage bypass. When this occurs has been debated. It is now shown that PRR can be postponed until much of the undamaged genome is replicated. Moreover, it seems that PRR occurs mainly by an error-prone process, with error-free bypass playing a minor role.

    • Yasukazu Daigaku
    • , Adelina A. Davies
    •  & Helle D. Ulrich

  • Letter |

    Most agents that generate breaks in DNA leave 'dirty ends' that cannot be joined immediately; instead, intervening steps are required to restore the integrity of nucleotides at the break. Here it is shown that the non-homologous end joining pathway requires a 5′-dRP/AP lyase activity to remove abasic sites at double-strand breaks. Surprisingly, this activity is catalysed by the Ku70 protein, which, together with its partner Ku86, had been thought only to recognize broken DNA ends and to recruit other factors that process ends.

    • Steven A. Roberts
    • , Natasha Strande
    •  & Dale A. Ramsden

  • Letter |

    In meiotic cells paired homologues are joined by a set of crossovers known as a double Holliday junction (DHJ). Whether DHJs form during mitotic recombination has been unclear, as mitotic cells possess alternative repair pathways that would not require DHJ formation. Here it is demonstrated that mitotic and meiotic cells form similar DHJs, but that the levels in mitotic cells are approximately 10–fold lower, and show a preference for joints between sister chromatids rather than homologues. Consequently, in mitotic cells non–crossover outcomes are favoured.

    • Malgorzata Bzymek
    • , Nathaniel H. Thayer
    •  & Neil Hunter

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