Special Issue "DNA Damage Response"

Guest Editor
Prof. Dr. Wolf-Dietrich Heyer
Department of Microbiology, University of California, Davis, One Shields Avenue, Davis, CA 95616, USA
Website: http://micro.ucdavis.edu/heyer
E-Mail: wdheyer@ucdavis.edu
Phone: +1 530 752 3001
Fax: +1 530 752 3011
Interests: regulation and mechanisms of homologous recombination; genome stability; DNA damage response

Guest Editor
Prof. Dr. Thomas Helleday
¹ Gray Institute for Radiation Oncology and Biology, University of Oxford, Oxford OX3 7DQ, UK
² Department of Genetics, Microbiology and Toxicology, Stockholm University, S-106 91 Stockholm, Sweden
Website: http://www.rob.ox.ac.uk/research/researchgroups/thomas-helleday
E-Mail: thomas.helleday@scilifelab.se
Phone: +44 1865 617337
Fax: +44 1865 617334
Interests: DNA damage signalling; homologous recombination at replication forks in mammalian cells

Guest Editor
Prof. Dr. Fumio Hanaoka
Department of Life Science, Faculty of Science, Gakushuin University, 1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588, Japan
Website: http://www.jsps.go.jp/j-bilat/semin/gan_report/2000_cancer/hanaoka.html
E-Mail: fumio.hanaoka@gakushuin.ac.jp
Phone: +81 3 3986 0221 ext. 6457
Fax: +81 3 5992 1029
Interests: molecular mechanisms of translesion synthesis and nucleotide excision repair; understanding the cellular responses to DNA damages; interactions between cell cycle control and DNA repair

Dear Colleagues,

In two ground breaking publications in Science in 1988/1989, Ted Weinert and Lee Hartwell conceptualized many previous observations on how cells react to genotoxic stress by developing the checkpoint model. They validated the concept by isolating the first DNA damage checkpoint mutant in the budding yeast Saccharomyces cerevisiae and showing that RAD9 controlled transient cell cycle arrest after ionizing radiation exposure. These seminal discoveries propelled an entire field that is still thriving. We realize over 20 years later that the cell cycle response is only one, albeit critical aspect, of a much broader cellular answer to genotoxic stress that is now called the DNA Damage Response. This issue intends to showcase up to date reviews about emerging concepts from future leaders in this exciting area of research.

We thus invite submission review manuscripts (although original research manuscripts are welcome as well) that cover any aspect of the DNA damage response, a complex web of interconnected pathways that control many cellular processes including DNA replication, DNA repair, the mitotic and meiotic cell cycle, and nuclear architecture. The DNA damage response is intricately linked to cancer. Defects in the DNA damage response predispose humans to cancer, and many forms of anti-cancer treatment involve inducing localized or systemic DNA damage. Thus insights into the fundamental mechanisms of the DNA damage response are poised for translation into clinical practice.

We look forward to reading your contributions.

Prof. Dr. Wolf-Dietrich Heyer
Prof. Dr. Thomas Helleday
Prof. Dr. Fumio Hanaoka
Guest Editors

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• DNA damage
• DNA checkpoints
• DNA repair
• DNA replication
• genome instability
• heterochromatin
• cell cycle control

Title: Homologous Recombination as a Replication Fork Escort: Fork-protection and Recovery
Authors: Audrey Costes ^1,2 and Sarah Lambert ^1,2
Affiliations: ¹ Institut Curie, Centre de Recherche, France
² CNRS, UMR3348, Centre Universitaire, Bat110, 91405, Orsay, France; E-Mail: sarah.lambert@curie.fr (S.L.)
Abstract: Homologous recombination is a universal mechanism that promotes DNA repair and supports DNA replication. The basic function of homologous recombination is to promote a strand exchange reaction that ultimately results in a genetic exchange. Thus, homologous recombination is a fundamental process promoting genetic diversity both during conjugation in prokaryotes and during meiosis in eukaryotes. Whereas the role of homologous recombination during the repair of double strand break has been extensively studies and it is now well characterized, the function of homologous recombination as a support for DNA replication remains poorly understood in eukaryotes. Nonetheless, studies in bacteria have enlightened multiple roles for homologous recombination at replication forks. Here, we review our understanding of the molecular pathways involving homologous recombination to support faithful DNA replication. Beyond its role in fork-repair and in rebuilding a functional replication fork apparatus, homologous recombination might also acts as a fork-protection mechanism. We speculate that this last function might be independent of the ability of homologous recombination to perform a strand exchange reaction and we refer to this mechanism as a Strand Exchange Free event (SEX-free recombination).

Type of Paper: Article
Title: Human DNA Glycosylase NEIL1’s Interactions with Downstream Repair Proteins Is Critical for Efficient Repair of Oxidized Genome Damage and Cell Survival
Authors: Muralidhar L. Hegde^1,2, Pavana M. Hegde¹, Arijit Dutta¹ and Sankar Mitra^1,3,*
Affiliations: ¹ Departments of Biochemistry and Molecular Biology, University of Texas Medical Branch (UTMB) at Galveston, Texas 77555, USA
² Departments of Neurology, University of Texas Medical Branch (UTMB) at Galveston, Texas 77555, USA
³ Departments of Sealy Center for Molecular Medicine, University of Texas Medical Branch (UTMB) at Galveston, Texas 77555, USA; E-Mails: mlhegde@utmb.edu (M.L.H.); padixit@utmb.edu (P.M.H.); ardutta@utmb.edu (A.D.); samitra@utmb.edu (S.M.)
Abstract: NEIL1 is unique among the oxidative base damage repair-initiating DNA glycosylases in the human genome for its S phase specific activation and ability to excise substrate base lesions from single-stranded DNA. We recently characterized NEIL1’s specific binding to several downstream conventional repair and non-canonical accessory proteins, all of which involves NEIL1’s disordered, C-terminal segment as the common interaction domain (CID). This domain is dispensable for NEIL1’s lesion excision and abasic (AP) lyase activities but is required for their enhancement via interactions with downstream partner proteins. Here, we show that truncated NEIL1 lacking the CID is markedly deficient in initiating in vitro repair of 5-hydroxyuracil (oxidative deamination product of C) present in a plasmid, compared to the wild type NEIL1, suggesting the critical role of CID in coordination of overall repair. Furthermore, while NEIL1 downregulation significantly sensitized human embryonic kidney (HEK) 293 cells to reactive oxygen species (ROS), as expected, ectopic wild type NEIL1, but not the truncated mutant, complemented ROS sensitivity. These results demonstrate that NEIL-dependent repair of oxidative DNA base damage and cell survival requires interaction among repair proteins which could be exploited as a therapeutic target in cancer for increasing the efficiency of chemo/radiation treatment.
Keywords: NEIL1; DNA glycosylase; base excision repair; protein-protein interaction; reactive oxygen species; common interaction domain; disordered structure