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James W. Halbrook

Bio: James W. Halbrook is an academic researcher from Icos. The author has contributed to research in topics: Replication protein A & Biological activity. The author has an hindex of 2, co-authored 2 publications receiving 266 citations.

Papers
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Journal ArticleDOI
TL;DR: Results show that PARP can modify the activity of DNA-PK in vitro and suggest that these enzymes may function coordinately in vivo in response to DNA damage.

244 citations

Patent
19 Mar 2004
TL;DR: In this article, compositions comprising the compounds, methods of inhibiting the DNA-PK biological activity, and methods of sensitizing cells the agents that cause DNA lesions, and method of potentiating cancer treatment are disclosed.
Abstract: Compound that inhibit DNA-dependent protein kinase, compositions comprising the compounds, methods of inhibiting the DNA-PK biological activity, methods of sensitizing cells the agents that cause DNA lesions, and methods of potentiating cancer treatment are disclosed.

33 citations


Cited by
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Journal ArticleDOI
20 Nov 1998-Science
TL;DR: Tankyrase, a protein with homology to ankyrins and to the catalytic domain of poly(adenosine diphosphate-ribose) polymerase (PARP), was identified and localized to human telomeres.
Abstract: Tankyrase, a protein with homology to ankyrins and to the catalytic domain of poly(adenosine diphosphate-ribose) polymerase (PARP), was identified and localized to human telomeres. Tankyrase binds to the telomeric protein TRF1 (telomeric repeat binding factor-1), a negative regulator of telomere length maintenance. Like ankyrins, tankyrase contains 24 ankyrin repeats in a domain responsible for its interaction with TRF1. Recombinant tankyrase was found to have PARP activity in vitro, with both TRF1 and tankyrase functioning as acceptors for adenosine diphosphate (ADP)-ribosylation. ADP-ribosylation of TRF1 diminished its ability to bind to telomeric DNA in vitro, suggesting that telomere function in human cells is regulated by poly(ADP-ribosyl)ation.

1,035 citations

Journal ArticleDOI
TL;DR: The roles of PARP1 in mediating various aspects of DNA metabolism, such as single-strand break repair, nucleotide excision repair, double-stranded break repair and the stabilization of replication forks, and in modulating chromatin structure are discussed.
Abstract: Cells are exposed to various endogenous and exogenous insults that induce DNA damage, which, if unrepaired, impairs genome integrity and leads to the development of various diseases, including cancer. Recent evidence has implicated poly(ADP-ribose) polymerase 1 (PARP1) in various DNA repair pathways and in the maintenance of genomic stability. The inhibition of PARP1 is therefore being exploited clinically for the treatment of various cancers, which include DNA repair-deficient ovarian, breast and prostate cancers. Understanding the role of PARP1 in maintaining genome integrity is not only important for the design of novel chemotherapeutic agents, but is also crucial for gaining insights into the mechanisms of chemoresistance in cancer cells. In this Review, we discuss the roles of PARP1 in mediating various aspects of DNA metabolism, such as single-strand break repair, nucleotide excision repair, double-strand break repair and the stabilization of replication forks, and in modulating chromatin structure.

928 citations

Journal ArticleDOI
TL;DR: Studies on DNA-PK should provide a better understanding of degenerative disease and cancer, and may lead to improved therapies for these conditions, as well as related proteins involved in DNA damage detection.
Abstract: The DNA-dependent protein kinase (DNA–PK) is anuclear serine/threonine protein kinase that is activatedupon association with DNA. Biochemical and geneticdata have revealed DNA–PK to be composed of a largecatalytic subunit, termed DNA–PKcs, and a regulatoryfactor termed Ku. In recent years, mammalian DNA–PKhas been shown to be a crucial component of both theDNA double-strand break (DSB) repair machinery andthe

902 citations

Journal ArticleDOI
TL;DR: It is shown that PARP-1 operates in an alternative pathway of non-homologous end joining (NHEJ) that functions as backup to the classical pathway of NHEJ that utilizes DNA-PKcs, Ku, DNA ligase IV, XRCC4, XLF/Cernunnos and Artemis.
Abstract: Poly(ADP-ribose)polymerase 1 (PARP-1) recognizes DNA strand interruptions in vivo and triggers its own modification as well as that of other proteins by the sequential addition of ADP-ribose to form polymers. This modification causes a release of PARP-1 from DNA ends and initiates a variety of responses including DNA repair. While PARP-1 has been firmly implicated in base excision and single strand break repair, its role in the repair of DNA double strand breaks (DSBs) remains unclear. Here, we show that PARP-1, probably together with DNA ligase III, operates in an alternative pathway of non-homologous end joining (NHEJ) that functions as backup to the classical pathway of NHEJ that utilizes DNA-PKcs, Ku, DNA ligase IV, XRCC4, XLF/Cernunnos and Artemis. PARP-1 binds to DNA ends in direct competition with Ku. However, in irradiated cells the higher affinity of Ku for DSBs and an excessive number of other forms of competing DNA lesions limit its contribution to DSB repair. When essential components of the classical pathway of NHEJ are absent, PARP-1 is recruited for DSB repair, particularly in the absence of Ku and non-DSB lesions. This form of DSB repair is sensitive to PARP-1 inhibitors. The results define the function of PARP-1 in DSB repair and characterize a candidate pathway responsible for joining errors causing genomic instability and cancer.

792 citations

Journal ArticleDOI
TL;DR: This review highlights recent work on the biochemistry, molecular biology, physiology, and pathophysiology of PARylation, focusing on the activity ofPARP-1, the most abundantly expressed member of a family of PARP proteins.
Abstract: Poly(ADP-ribose) (PAR) and the PAR polymerases (PARPs) that catalyze its synthesis from donor nicotinamide adenine dinucleotide (NAD+) molecules have received considerable attention in the recent literature. Poly(ADP-ribosyl)ation (PARylation) plays diverse roles in many molecular and cellular processes, including DNA damage detection and repair, chromatin modification, transcription, cell death pathways, insulator function, and mitotic apparatus function. These processes are critical for many physiological and pathophysiological outcomes, including genome maintenance, carcinogenesis, aging, inflammation, and neuronal function. This review highlights recent work on the biochemistry, molecular biology, physiology, and pathophysiology of PARylation, focusing on the activity of PARP-1, the most abundantly expressed member of a family of PARP proteins. In addition, connections between nuclear NAD+ metabolism and nuclear signaling through PARP-1 are discussed.

790 citations