Biomolecules

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Open AccessReview

Strategies for the Use of Poly(adenosine diphosphate ribose) Polymerase (PARP) Inhibitors in Cancer Therapy

by Cecilia E. Ström and Thomas Helleday

Biomolecules 2012, 2(4), 635-649; https://doi.org/10.3390/biom2040635 - 14 Dec 2012

Cited by 18 | Viewed by 10841

Treatments with Poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors have offered patients carrying cancers with mutated BRCA1 or BRCA2 genes a new and in many cases effective option for disease control. There is potentially a large patient population that may also benefit from PARP [...] Read more.

Treatments with Poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors have offered patients carrying cancers with mutated BRCA1 or BRCA2 genes a new and in many cases effective option for disease control. There is potentially a large patient population that may also benefit from PARP inhibitor treatment, either in monotherapy or in combination with chemotherapy. Here, we describe the multifaceted role of PARP inhibitors and discuss which treatment options could potentially be useful to gain disease control without potentiating side effects. Full article

(This article belongs to the Special Issue DNA Damage Response)

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Open AccessArticle

Decorin Content and Near Infrared Spectroscopy Analysis of Dried Collagenous Biomaterial Samples

by Mila L. Aldema-Ramos, Joan Carles Castell, Zerlina E. Muir, Jose Maria Adzet, Rosa Sabe and Suzanne Schreyer

Biomolecules 2012, 2(4), 622-634; https://doi.org/10.3390/biom2040622 - 14 Dec 2012

Cited by 1 | Viewed by 8262

Abstract

The efficient removal of proteoglycans, such as decorin, from the hide when processing it to leather by traditional means is generally acceptable and beneficial for leather quality, especially for softness and flexibility. A patented waterless or acetone dehydration method that can generate a [...] Read more.

The efficient removal of proteoglycans, such as decorin, from the hide when processing it to leather by traditional means is generally acceptable and beneficial for leather quality, especially for softness and flexibility. A patented waterless or acetone dehydration method that can generate a product similar to leather called Dried Collagenous Biomaterial (known as BCD) was developed but has no effect on decorin removal efficiency. The Alcian Blue colorimetric technique was used to assay the sulfated glycosaminoglycan (sGAG) portion of decorin. The corresponding residual decorin content was correlated to the mechanical properties of the BCD samples and was comparable to the control leather made traditionally. The waterless dehydration and instantaneous chrome tanning process is a good eco-friendly alternative to transforming hides to leather because no additional effects were observed after examination using NIR spectroscopy and additional chemometric analysis. Full article

(This article belongs to the Special Issue DNA Damage Response)

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Open AccessReview

Emerging Roles for Non-Coding RNAs in Male Reproductive Development in Flowering Plants

by Robert Grant-Downton and Josefina Rodriguez-Enriquez

Biomolecules 2012, 2(4), 608-621; https://doi.org/10.3390/biom2040608 - 4 Dec 2012

Cited by 9 | Viewed by 9507

Abstract

Knowledge of sexual reproduction systems in flowering plants is essential to humankind, with crop fertility vitally important for food security. Here, we review rapidly emerging new evidence for the key importance of non-coding RNAs in male reproductive development in flowering plants. From the [...] Read more.

Knowledge of sexual reproduction systems in flowering plants is essential to humankind, with crop fertility vitally important for food security. Here, we review rapidly emerging new evidence for the key importance of non-coding RNAs in male reproductive development in flowering plants. From the commitment of somatic cells to initiating reproductive development through to meiosis and the development of pollen—containing the male gametes (sperm cells)—in the anther, there is now overwhelming data for a diversity of non-coding RNAs and emerging evidence for crucial roles for them in regulating cellular events at these developmental stages. A particularly exciting development has been the association of one example of cytoplasmic male sterility, which has become an unparalleled breeding tool for producing new crop hybrids, with a non-coding RNA locus. Full article

(This article belongs to the Special Issue Non-coding RNA)

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Pathways for Genome Integrity in G2 Phase of the Cell Cycle

by Arne Nedergaard Kousholt, Tobias Menzel and Claus Storgaard Sørensen

Biomolecules 2012, 2(4), 579-607; https://doi.org/10.3390/biom2040579 - 30 Nov 2012

Cited by 30 | Viewed by 9969 | Correction

Abstract

The maintenance of genome integrity is important for normal cellular functions, organism development and the prevention of diseases, such as cancer. Cellular pathways respond immediately to DNA breaks leading to the initiation of a multi-facetted DNA damage response, which leads to DNA repair [...] Read more.

The maintenance of genome integrity is important for normal cellular functions, organism development and the prevention of diseases, such as cancer. Cellular pathways respond immediately to DNA breaks leading to the initiation of a multi-facetted DNA damage response, which leads to DNA repair and cell cycle arrest. Cell cycle checkpoints provide the cell time to complete replication and repair the DNA damage before it can continue to the next cell cycle phase. The G2/M checkpoint plays an especially important role in ensuring the propagation of error-free copies of the genome to each daughter cell. Here, we review recent progress in our understanding of DNA repair and checkpoint pathways in late S and G2 phases. This review will first describe the current understanding of normal cell cycle progression through G2 phase to mitosis. It will also discuss the DNA damage response including cell cycle checkpoint control and DNA double-strand break repair. Finally, we discuss the emerging concept that DNA repair pathways play a major role in the G2/M checkpoint pathway thereby blocking cell division as long as DNA lesions are present. Full article

(This article belongs to the Special Issue DNA Damage Response)

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Open AccessArticle

Human DNA Glycosylase NEIL1’s Interactions with Downstream Repair Proteins Is Critical for Efficient Repair of Oxidized DNA Base Damage and Enhanced Cell Survival

by Muralidhar L. Hegde, Pavana M. Hegde, Dutta Arijit, Istvan Boldogh and Sankar Mitra

Biomolecules 2012, 2(4), 564-578; https://doi.org/10.3390/biom2040564 - 15 Nov 2012

Cited by 33 | Viewed by 10810

Abstract

NEIL1 is unique among the oxidatively damaged base repair-initiating DNA glycosylases in the human genome due to its S phase-specific activation and ability to excise substrate base lesions from single-stranded DNA. We recently characterized NEIL1’s specific binding to downstream canonical repair and non-canonical [...] Read more.

NEIL1 is unique among the oxidatively damaged base repair-initiating DNA glycosylases in the human genome due to its S phase-specific activation and ability to excise substrate base lesions from single-stranded DNA. We recently characterized NEIL1’s specific binding to downstream canonical repair and non-canonical accessory proteins, all of which involve NEIL1’s disordered C-terminal segment as the common interaction domain (CID). This domain is dispensable for NEIL1’s base excision and abasic (AP) lyase activities, but is required for its interactions with other repair proteins. Here, we show that truncated NEIL1 lacking the CID is markedly deficient in initiating in vitro repair of 5-hydroxyuracil (an oxidative deamination product of C) in a plasmid substrate compared to the wild-type NEIL1, thus suggesting a critical role of CID in the coordination of overall repair. Furthermore, while NEIL1 downregulation significantly sensitized human embryonic kidney (HEK) 293 cells to reactive oxygen species (ROS), ectopic wild-type NEIL1, but not the truncated mutant, restored resistance to ROS. These results demonstrate that cell survival and NEIL1-dependent repair of oxidative DNA base damage require interactions among repair proteins, which could be explored as a cancer therapeutic target in order to increase the efficiency of chemo/radiation treatment. Full article

(This article belongs to the Special Issue DNA Damage Response)

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Open AccessArticle

Hyaluronidases Have Strong Hydrolytic Activity toward Chondroitin 4-Sulfate Comparable to that for Hyaluronan

by Tomoko Honda, Tomoyuki Kaneiwa, Shuji Mizumoto, Kazuyuki Sugahara and Shuhei Yamada

Biomolecules 2012, 2(4), 549-563; https://doi.org/10.3390/biom2040549 - 12 Nov 2012

Cited by 52 | Viewed by 9363

Abstract

Chondroitin sulfate (CS) chains are involved in the regulation of various biological processes. However, the mechanism underlying the catabolism of CS is not well understood. Hyaluronan (HA)-degrading enzymes, the hyaluronidases, are assumed to act at the initial stage of the degradation process, because [...] Read more.

Chondroitin sulfate (CS) chains are involved in the regulation of various biological processes. However, the mechanism underlying the catabolism of CS is not well understood. Hyaluronan (HA)-degrading enzymes, the hyaluronidases, are assumed to act at the initial stage of the degradation process, because HA is similar in structure to nonsulfated CS, chondroitin (Chn). Although human hyaluronidase-1 (HYAL1) and testicular hyaluronidase (SPAM1) can degrade not only HA but also CS, they are assumed to digest CS to only a limited extent. In this study, the hydrolytic activities of HYAL1 and SPAM1 toward CS-A, CS-C, Chn, and HA were compared. HYAL1 depolymerized CS-A and HA to a similar extent. SPAM1 degraded CS-A, Chn, and HA to a similar extent. CS is widely distributed from very primitive organisms to humans, whereas HA has been reported to be present only in vertebrates with the single exception of a mollusk. Therefore, a genuine substrate of hyaluronidases appears to be CS as well as HA. Full article

(This article belongs to the Special Issue Challenges in Glycan, Glycoprotein and Proteoglycan Research)

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594 KiB

Open AccessReview

Functional Aspects of PARP1 in DNA Repair and Transcription

by Hui Ling Ko and Ee Chee Ren

Biomolecules 2012, 2(4), 524-548; https://doi.org/10.3390/biom2040524 - 12 Nov 2012

Cited by 144 | Viewed by 22089

Abstract

Poly (ADP-ribose) polymerase 1 (PARP1) is an ADP-ribosylating enzyme essential for initiating various forms of DNA repair. Inhibiting its enzyme activity with small molecules thus achieves synthetic lethality by preventing unwanted DNA repair in the treatment of cancers. Through enzyme-dependent chromatin remodeling and [...] Read more.

Poly (ADP-ribose) polymerase 1 (PARP1) is an ADP-ribosylating enzyme essential for initiating various forms of DNA repair. Inhibiting its enzyme activity with small molecules thus achieves synthetic lethality by preventing unwanted DNA repair in the treatment of cancers. Through enzyme-dependent chromatin remodeling and enzyme-independent motif recognition, PARP1 also plays important roles in regulating gene expression. Besides presenting current findings on how each process is individually controlled by PARP1, we shall discuss how transcription and DNA repair are so intricately linked that disturbance by PARP1 enzymatic inhibition, enzyme hyperactivation in diseases, and viral replication can favor one function while suppressing the other. Full article

(This article belongs to the Special Issue DNA Damage Response)

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538 KiB

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Preserving Yeast Genetic Heritage through DNA Damage Checkpoint Regulation and Telomere Maintenance

by Veronica Baldo, Jason Liang, Guoliang Wang and Huilin Zhou

Biomolecules 2012, 2(4), 505-523; https://doi.org/10.3390/biom2040505 - 30 Oct 2012

Cited by 3 | Viewed by 10698

Abstract

In order to preserve genome integrity, extrinsic or intrinsic DNA damages must be repaired before they accumulate in cells and trigger other mutations and genome rearrangements. Eukaryotic cells are able to respond to different genotoxic stresses as well as to single DNA double [...] Read more.

In order to preserve genome integrity, extrinsic or intrinsic DNA damages must be repaired before they accumulate in cells and trigger other mutations and genome rearrangements. Eukaryotic cells are able to respond to different genotoxic stresses as well as to single DNA double strand breaks (DSBs), suggesting highly sensitive and robust mechanisms to detect lesions that trigger a signal transduction cascade which, in turn, controls the DNA damage response (DDR). Furthermore, cells must be able to distinguish natural chromosomal ends from DNA DSBs in order to prevent inappropriate checkpoint activation, DDR and chromosomal rearrangements. Since the original discovery of RAD9, the first DNA damage checkpoint gene identified in Saccharomyces cerevisiae, many genes that have a role in this pathway have been identified, including MRC1, MEC3, RAD24, RAD53, DUN1, MEC1 and TEL1. Extensive studies have established most of the genetic basis of the DNA damage checkpoint and uncovered its different functions in cell cycle regulation, DNA replication and repair, and telomere maintenance. However, major questions concerning the regulation and functions of the DNA damage checkpoint remain to be answered. First, how is the checkpoint activity coupled to DNA replication and repair? Second, how do cells distinguish natural chromosome ends from deleterious DNA DSBs? In this review we will examine primarily studies performed using Saccharomyces cerevisiae as a model system. Full article

(This article belongs to the Special Issue DNA Damage Response)

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Break-Induced Replication and Genome Stability

by Cynthia J. Sakofsky, Sandeep Ayyar and Anna Malkova

Biomolecules 2012, 2(4), 483-504; https://doi.org/10.3390/biom2040483 - 16 Oct 2012

Cited by 26 | Viewed by 12554

Abstract

Genetic instabilities, including mutations and chromosomal rearrangements, lead to cancer and other diseases in humans and play an important role in evolution. A frequent cause of genetic instabilities is double-strand DNA breaks (DSBs), which may arise from a wide range of exogeneous and [...] Read more.

Genetic instabilities, including mutations and chromosomal rearrangements, lead to cancer and other diseases in humans and play an important role in evolution. A frequent cause of genetic instabilities is double-strand DNA breaks (DSBs), which may arise from a wide range of exogeneous and endogeneous cellular factors. Although the repair of DSBs is required, some repair pathways are dangerous because they may destabilize the genome. One such pathway, break-induced replication (BIR), is the mechanism for repairing DSBs that possesses only one repairable end. This situation commonly arises as a result of eroded telomeres or collapsed replication forks. Although BIR plays a positive role in repairing DSBs, it can alternatively be a dangerous source of several types of genetic instabilities, including loss of heterozygosity, telomere maintenance in the absence of telomerase, and non-reciprocal translocations. Also, mutation rates in BIR are about 1000 times higher as compared to normal DNA replication. In addition, micro-homology-mediated BIR (MMBIR), which is a mechanism related to BIR, can generate copy-number variations (CNVs) as well as various complex chromosomal rearrangements. Overall, activation of BIR may contribute to genomic destabilization resulting in substantial biological consequences including those affecting human health. Full article

(This article belongs to the Special Issue DNA Damage Response)

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Open AccessReview

Glycobiology Aspects of the Periodontal Pathogen Tannerella forsythia

by Gerald Posch, Gerhard Sekot, Valentin Friedrich, Zoë A. Megson, Andrea Koerdt, Paul Messner and Christina Schäffer

Biomolecules 2012, 2(4), 467-482; https://doi.org/10.3390/biom2040467 - 12 Oct 2012

Cited by 24 | Viewed by 10055

Abstract

Glycobiology is important for the periodontal pathogen Tannerella forsythia, affecting the bacterium’s cellular integrity, its life-style, and virulence potential. The bacterium possesses a unique Gram-negative cell envelope with a glycosylated surface (S-) layer as outermost decoration that is proposed to be [...] Read more.

Glycobiology is important for the periodontal pathogen Tannerella forsythia, affecting the bacterium’s cellular integrity, its life-style, and virulence potential. The bacterium possesses a unique Gram-negative cell envelope with a glycosylated surface (S-) layer as outermost decoration that is proposed to be anchored via a rough lipopolysaccharide. The S-layer glycan has the structure 4‑MeO-b-ManpNAcCONH₂-(1→3)-[Pse5Am7Gc-(2→4)-]-b-ManpNAcA-(1→4)-[4-MeO-a-Galp-(1→2)-]-a-Fucp-(1→4)-[-a-Xylp-(1→3)-]-b-GlcpA-(1→3)-[-b-Digp-(1→2)-]-a-Galp and is linked to distinct serine and threonine residues within the D(S/T)(A/I/L/M/T/V) amino acid motif. Also several other Tannerella proteins are modified with the S‑layer oligosaccharide, indicating the presence of a general O‑glycosylation system. Protein O‑glycosylation impacts the life-style of T. forsythia since truncated S-layer glycans present in a defined mutant favor biofilm formation. While the S‑layer has also been shown to be a virulence factor and to delay the bacterium's recognition by the innate immune system of the host, the contribution of glycosylation to modulating host immunity is currently unraveling. Recently, it was shown that Tannerella surface glycosylation has a role in restraining the Th17-mediated neutrophil infiltration in the gingival tissues. Related to its asaccharolytic physiology, T. forsythia expresses a robust enzymatic repertoire, including several glycosidases, such as sialidases, which are linked to specific growth requirements and are involved in triggering host tissue destruction. This review compiles the current knowledge on the glycobiology of T. forsythia. Full article

(This article belongs to the Special Issue Challenges in Glycan, Glycoprotein and Proteoglycan Research)

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Open AccessReview

Sialyl-Tn in Cancer: (How) Did We Miss the Target?

by Sylvain Julien, Paula A. Videira and Philippe Delannoy

Biomolecules 2012, 2(4), 435-466; https://doi.org/10.3390/biom2040435 - 11 Oct 2012

Cited by 140 | Viewed by 20057

Abstract

Sialyl-Tn antigen (STn) is a short O-glycan containing a sialic acid residue a2,6-linked to GalNAca-O-Ser/Thr. The biosynthesis of STn is mediated by a specific sialyltransferase termed ST6GalNAc I, which competes with O-glycans elongating glycosyltransferases and prevents cancer cells from [...] Read more.

Sialyl-Tn antigen (STn) is a short O-glycan containing a sialic acid residue a2,6-linked to GalNAca-O-Ser/Thr. The biosynthesis of STn is mediated by a specific sialyltransferase termed ST6GalNAc I, which competes with O-glycans elongating glycosyltransferases and prevents cancer cells from exhibiting longer O-glycans. While weakly expressed by fetal and normal adult tissues, STn is expressed by more than 80% of human carcinomas and in all cases, STn detection is associated with adverse outcome and decreased overall survival for the patients. Because of its pan-carcinoma expression associated with an adverse outcome, an anti-cancer vaccine, named Theratope, has been designed towards the STn epitope. In spite of the great enthusiasm around this immunotherapy, Theratope failed on Phase III clinical trial. However, in lieu of missing this target, one should consider to revise the Theratope design and the actual facts. In this review, we highlight the many lessons that can be learned from this failure from the immunological standpoint, as well as from the drug design and formulation and patient selection. Moreover, an irrefutable knowledge is arising from novel immunotherapies targeting other carbohydrate antigens and STn carrier proteins, such as MUC1, that will warrantee the future development of more successful anti-STn immunotherapy strategies. Full article

(This article belongs to the Special Issue Challenges in Glycan, Glycoprotein and Proteoglycan Research)

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Promiscuity of the Euonymus Carbohydrate-Binding Domain

by Elke Fouquaert and Els J.M. Van Damme

Biomolecules 2012, 2(4), 415-434; https://doi.org/10.3390/biom2040415 - 8 Oct 2012

Cited by 24 | Viewed by 7952

Abstract

Plants synthesize small amounts of carbohydrate-binding proteins on exposure to stress. For example, on exposure to drought, high salt, wounding and by treatment with some plant hormones or by pathogen attack. In contrast to the ‘classical’ plant lectins that are mostly located in [...] Read more.

Plants synthesize small amounts of carbohydrate-binding proteins on exposure to stress. For example, on exposure to drought, high salt, wounding and by treatment with some plant hormones or by pathogen attack. In contrast to the ‘classical’ plant lectins that are mostly located in the vacuolar compartment, this new class of inducible lectins is present in the cytoplasm and in the nucleus. Taking into account that any physiological role of plant lectins most likely relies on their specific carbohydrate-binding activity and specificity, the discovery of these stress-related lectins provides strong evidence for the importance of protein-carbohydrate-interactions in plant cells. Hitherto, six families of such nucleocytoplasmic lectins have been identified in plants. This review will focus on the nucleocytoplasmic lectins with one or more Euonymus lectin (EUL) domain(s). The carbohydrate-binding specificity of EUL proteins from a monocot, a dicot and a lower plant has been compared. Furthermore, modeling of the different EUL domains revealed a similar ß-trefoil fold consisting of three bundles of ß-sheet organized around a pseudo three-fold symmetry axis. Despite the sequence similarity and the conserved amino acids in the binding site, glycan array analyses showed that the EUL domain has a promiscuous carbohydrate-binding site capable of accommodating high mannose N-glycans, blood group B related structures and galactosylated epitopes. Full article

(This article belongs to the Special Issue Challenges in Glycan, Glycoprotein and Proteoglycan Research)

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Biomolecules, Volume 2, Issue 4 (December 2012) – 12 articles , Pages 415-649

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