Endogenous DNA Damage and Repair Enzymes—A short summary of the scientific achievements of Tomas Lindahl,Nobel Laureate in Chemistry 2015

Tomas Lindahl completed his medical studies at Karolinska Institute in 1970. Yet, his work has always been dedicated to unraveling fundamental mechanisms of DNA decay and DNA repair. His research is characterized with groundbreaking discoveries on the instability of our genome, the identification of novel DNA repair activities, the characterization of DNA repair pathways, and the association to diseases, throughout his 40 years of scientific career.     

Base-excision repair and beyond—A short summary attributed to scientific achievements of Tomas Lindahl,Nobel Prize Laureate in Chemistry 2015

正Tomas Lindahl contributed his scientific career to unveiling fundamental mechanisms of DNA decay and repair.He made several ground-breaking discoveries on genome instability,novel DNA repair activities and pathways,and disease association.The 2015 Nobel Prize in Chemistry was awarded jointly to Tomas Lindahl,Paul Modrich and Aziz Sancar for their mechanistic studies of DNA repair.Their findings were     

My Journey to DNA Repair

I completed my medical studies at the Karolinska Institute in Stockholm but have always been devoted to basic research. My longstanding interest is to understand fundamental DNA repair mechanisms in the fields of cancer therapy, inherited human genetic disorders and ancient DNA. I initially measured DNA decay, including rates of base loss and cytosine deamination. I have discovered several important DNA repair proteins and determined their mechanisms of action. The discovery of uracil-DNA glycosylase defined a new category of repair enzymes with each specialized for different types of DNA damage. The base excision repair pathway was first reconstituted with human proteins in my group. Cell-free analysis for mammalian nucleotide excision repair of DNA was also developed in my laboratory. I found multiple distinct DNA ligases in mammalian cells, and led the first genetic and biochemical work on DNA ligases Ⅰ, and Ⅳ. I discovered the mammalian exonucleases DNase Ⅲ (TREX1) and IV (FEN1). Interestingly, expression of TREX1 was altered in some human autoimmune diseases. I also showed that the mutagenic DNA adduct O6-methylguanine (O6 mG) is repaired without removing the guanine from DNA, identifying a surprising mechanism by which the methyl group is transferred to a residue in the repair protein itself. A further novel process of DNA repair discovered by my research group is the action of AlkB as an iron-dependent enzyme carrying out oxidative demethylation.     

The Nobel Prize in Chemistry 2015: Exciting discoveries in DNA repair by Aziz Sancar

正INTRODUCTION On October 7,2015,the Nobel Prize in Chemistry for 2015was awarded to three deserving scientists for their pioneering research on DNA repair.Tomas Lindahl was recognized for studies that uncovered the inherent instability of DNA as well as the mechanism of the base excision repair pathway,Paul Modrich for characterization of the mismatch repair     

Homologous recombination in DNA repair and DNA damage tolerance

Homologous recombination （HR） comprises a series of interrelated pathways that function in the repair of DNA double-stranded breaks （DSBs） and interstrand crosslinks （ICLs）. In addition, recombination provides critical support for DNA replication in the recovery of stalled or broken replication forks, contributing to tolerance of DNA damage. A central core of proteins, most critically the RecA homolog Rad51, catalyzes the key reactions that typify HR： homology search and DNA strand invasion. The diverse functions of recombination are reflected in the need for context-specific factors that perform supplemental functions in conjunction with the core proteins. The inability to properly repair complex DNA damage and resolve DNA replication stress leads to genomic instability and contributes to cancer etiology. Mutations in the BRCA2 recombination gene cause predisposition to breast and ovarian cancer as well as Fanconi anemia, a cancer predisposition syndrome characterized by a defect in the repair of DNA interstrand crosslinks. The cellular functions of recombination are also germane to DNA-based treatment modalities of cancer, which target replicating cells by the direct or indirect induction of DNA lesions that are substrates for recombination pathways. This review focuses on mechanistic aspects of HR relating to DSB and ICL repair as well as replication fork support.     

CHK2 kinase in the DNA damage response and beyond

The serine/threonine kinase CHK2 is a keycomponent of the DNA damage response. In human cells, following genotoxic stress, CHK2 is activated and phosphorylates 〉20 proteins to induce the appropriate cellular response, which, depending on the extent of damage, the cell type, and other factors, could be cell cycle checkpoint activation, induction of apoptosis or senescence, DNA repair, or tolerance of the damage. Recently, CHK2 has also been found to have cellular functions independent of the presence of nuclear DNA lesions. In par- ticular, CHK2 participates in several molecular processes involved in DNA structure modification and cell cycle progression. In this review, we discuss the activity of CHK2 in response to DNA damage and in the maintenance of the biological functions in unstressed cells. These activities are also considered in relation to a possible role of CHK2 in tumorigenesis and, as a consequence, as a target of cancer therapy.     

The role of NBS1 in DNA double strand break repair, telomere stability, and cell cycle checkpoint control

The genomes of eukaryotic cells are under continuous assault by environmental agents and endogenous metabolic byproducts. Damage induced in DNA usually leads to a cascade of cellular events, the DNA damage response. Failure of the DNA damage response can lead to development of malignancy by reducing the efficiency and fidelity of DNA repair. The NBS1 protein is a component of the MRE11/RAD50/NBS 1 complex （MRN） that plays a critical role in the cellular response to DNA damage and the maintenance of chromosomal integrity. Mutations in the NBS1 gene are responsible for Nijmegen breakage syndrome （NBS）, a hereditary disorder that imparts an increased predisposition to development of malignancy. The phenotypic characteristics of cells isolated from NBS patients point to a deficiency in the repair of DNA double strand breaks. Here, we review the current knowledge of the role of NBS1 in the DNA damage response. Emphasis is placed on the role of NBS1 in the DNA double strand repair, modulation of the DNA damage sensing and signaling, cell cycle checkpoint control and maintenance oftelomere stability.     

XRCC1 and DNA polymerase β in cellular protection against cytotoxic DNA single-strand breaks

Single-strand breaks （SSBs） can occur in cells either directly, or indirectly following initiation of base excision repair （BER）. SSBs generally have blocked termini lacking the conventional 5＇-phosphate and 3＇-hydroxyl groups and require further processing prior to DNA synthesis and ligation. XRCC1 is devoid of any known enzymatic activity, but it can physically interact with other proteins involved in all stages of the overlapping SSB repair and BER pathways, including those that conduct the rate-limiting end-tailoring, and in many cases can stimulate their enzymatic activities. XRCC1^-/- mouse fibroblasts are most hypersensitive to agents that produce DNA lesions repaired by monofunctional glycosylase-initiated BER and that result in formation of indirect SSBs. A requirement for the deoxyribose phosphate lyase activity of DNA polymerase β （pol β） is specific to this pathway, whereas pol β is implicated in gap-filling during repair of many types of SSBs. Elevated levels of strand breaks, and diminished repair, have been demonstrated in MMS- treated XRCC1^-/-, and to a lesser extent in pol β^-/- cell lines, compared with wild-type cells. Thus a strong correlation is observed between cellular sensitivity to MMS and the ability of cells to repair MMS-induced damage. Exposure of wild-type and polβ^-/- cells to an inhibitor of PARP activity dramatically potentiates MMS-induced cytotoxicity. XRCC1^-/- cells are also sensitized by PARP inhibition demonstrating that PARP-mediated poly（ADP-ribosyl）ation plays a role in modulation of cytotoxicity beyond recruitment of XRCC 1 to sites of DNA damage.     

Special Issue on‘‘Computational Cardiology’’

<正>We are pleased to announce a special issue on‘‘Computational Cardiology’’of the journal Genomics,ProteomicsBioinformatics(GPB),aiming to provide a platform for high-quality papers focusing on the topic and we invite submissions for this special issue(to be published in the fall of 2015).Dr.Benjamin Meder(University of Heidelberg and German Center for Cardiovascular Research–DZHK     

Flexibility in the order of action and in the enzymology of the nuclease, polymerases, and ligase of vertebrate non-homologous DNA end joining： relevance to cancer, aging, and the immune system

Nonhomologous DNA end joining （NHEJ） is the primary pathway for repair of double-strand DNA breaks in human cells and in multicellular eukaryotes. The causes of double-strand breaks often fragment the DNA at the site of damage, resulting in the loss of information there. NHEJ does not restore the lost information and may resect additional nucleotides during the repair process. The ability to repair a wide range of overhang and damage configurations reflects the flexibility of the nuclease, polymerases, and ligase of NHEJ. The flexibility of the individual components also explains the large number of ways in which NHEJ can repair any given pair of DNA ends. The loss of information locally at sites of NHEJ repair may contribute to cancer and aging, but the action by NHEJ ensures that entire segments of chromosomes are not lost.     

Ribonucleotide reductase metallocofactor: assembly,maintenance and inhibition

Ribonucleotide rcductase （RNR） supplies cellular deoxyribonucleotidc triphosphates （dNTP） pools by converting ribonucleotides to the corresponding deoxy forms using radical-based chemistry. Eukaryotic RNR comprises a and β subunits： u contains the catalytic and ailosteric sites; β houses a diferric-tyrosyl radical cofactor （FeⅢ2-Y· ） that is required to initiates nucleotide reduction in α. Cells have evolved multi-layered mechanisms to regulate RNR level and activity in order to maintain the adequate sizes and ratios of their dNTP pools to ensure high- fidelity DNA replication and repair. The central role of RNR in nucleotide metabolism also makes it a proven target of chemotherapeutics. In this review, we discuss recent progress in understanding the function and regulation of eukaryofic RNRs, with a focus on studies revealing the cellular machineries involved in RNR metaUocofactor biosynthesis and its implication in RNR-targeting therapeutics.     

Systems Biology Brings Life Sciences Closer——Report on the China-UK Systems Biology Workshop 2005

The China-UK Systems held during June 20-21 Biology Workshop 2005 was in the National Science Park of Zhejiang University, Hangzhou, China. It was organized by the Institute of Bioinformatics, Zhejiang University, and was initiated by Prof. Dr. Jun Zhu （Zhejiang University） and Prof. Dr. John Findlay （University of Leeds, UK）. The workshop was part of the program called UK-China Partners in Science, a one-year campaign that was initiated by the British government to explore more collaborations between UK and China on science and technology. It was attended also by a representative of this program, Mr. Frank Yuan, senior science ＆ innovation officer. The idea of the workshop was to bring together experts with specialists in systems biology in order to promote the ＂natural partnership＂ between scientists from the two countries. The most important items of systcms biology considered at the workshop were： （1） New technologies and advances in systems biology; （2） Research developments in genomics and proteomics; （3） New methodologies and software in computational biology; （4） Research collaboration on systems biology between China and UK.     

Liposome mediated drug delivery for leukocyte adhesion deficieny I （LAD I）： Targeting the mutated gene ITGB2 and expression of CD18 protein

Leukocyte adhesion deficiency （LAD） I is a disorder caused due to mutations in a gene （ITGB2） located on chromosome 21 and encodes the β2 subunit of the leukocyte integrin molecules. This leads to defects in the adhesion of leukocytes on endothelial cells which further leads to recurrent microbial infections due to a decrease in the immune response. Base Excision Repair Mechanism （BER） is instrumental in repairing damaged DNA by removing mutated/ damaged bases. We have proposed a hypothesis for the treatment of LAD I by making use of the proteins/enzyme complexes responsible for base excision repair mechanism be introduced into the leukocytes via liposomes. This will target the mutated gene in the leukocytes （mostly neutrophils） and DNA repair will occur. The liposomes can be introduced into the patients via intravenous methods.     

The key residue for SSB-RecO interaction is dispensable for Deinococcus radiodurans DNA repair in vivo

The RecFOR DNA repair pathway is one of the major RecA-dependent recombinatorial repair pathways in bacteria and plays an important role in double-strand breaks repair. RecO, one of the major recombination mediator proteins in the RecFOR pathway, has been shown to assist RecA loading onto single-stranded binding protein （SSB） coated single-stranded DNA （ssDNA）. However, it has not been characterized whether the protein-protein interaction between RecO and SSB contributes to that process in vivo. Here, we identified the residue arginine-121 of Deinococcus radiodurans RecO （drRecO-R121） as the key residue for RecO-SSB interaction. The substitution of drRecO-R121 with alanine greatly abolished the binding of RecO to SSB but not the binding to RecR. Meanwhile, SSB-coated ssDNA annealing activity was also compromised by the mutation of the residue of drRecO. However, the drRecO-R121A strain showed only modest sensitivity to DNA damaging agents. Taking these data together, arginine-121 of drRecO is the key residue for SSB-RecO interaction, which may not play a vital role in the SSB displacement and RecA loading process of RecFOR DNA repair pathway in vivo.