Chemical Changes Induced in DNA by Ionizing Radiation

Hutchinson, Franklin

doi:10.1016/s0079-6603(08)60347-5

Cited by 541 publications

(251 citation statements)

References 126 publications

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“…These di erences might be related to the type of induced genetic alteration. While MNU usually produces point mutations and alkylation in the DNA (Richardson et al, 1987), radiation can cause di erent kinds of DNA damage, including base alterations, deletions, insertions and internal rearrangements (Hutchinson, 1985). In concordance with this, although g-radiation-induced lymphomas are frequently deleted in a chromosome 4 region named TLSR1, no LOH in this region has been found in tumors induced by MNU treatment (Santos et al, 1996).…”

Section: Mouse P15 Ink4b and P16 Ink4a Cpg Islands Are Hypermethylatementioning

confidence: 94%

Inactivation of the cyclin-dependent kinase inhibitor p15INK4b by deletion and de novo methylation with independence of p16INK4a alterations in murine primary T-cell lymphomas

et al. 1997

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A wide panel of murine induced T-cell lymphomas have been analysed for p16 INK4a or p15 INK4b alterations. Only one g-radiation-induced lymphoma showed p16 INK4a homozygous deletion and no other intragenic mutations were found in these INK4 genes. However, de novo methylation of the 5' CpG islands of the murine p15 INK4b and p16 INK4a genes was found to be highly frequent. While p16 INK4a hypermethylation was found in 36% of the neutron-radiation-induced lymphomas and 15% of the gradiation-induced lymphomas, de novo methylation of p15 INK4b occurs in 88% and 42% of these tumors respectively, correlating with de®cient expression of the corresponding mRNA and allelic losses in the p15 INK4b and p16 INK4a chromosome location. These data represent, to our knowledge, the ®rst report on the signi®cant involvement of hypermethylation of these INK4 genes in murine primary tumors. Moreover, they show the importance of allelic losses and CpG island methylation of p15 INK4b gene inactivation and support a tumor suppressor role for p15 INK4b in T-cell lymphomas independent of p16 INK4a .

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Section: Mouse P15 Ink4b and P16 Ink4a Cpg Islands Are Hypermethylatementioning

confidence: 94%

Inactivation of the cyclin-dependent kinase inhibitor p15INK4b by deletion and de novo methylation with independence of p16INK4a alterations in murine primary T-cell lymphomas

et al. 1997

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“…This feature is essential for the rejoining of radiation-induced DSBs, which usually occur by free radical-mediated fragmentation of DNA sugars (Hutchinson, 1985;Isildar et al, 1981;Ward, 1988). If the stagger between breaks in each strand (which presumably is random) is at least two nucleotide positions, the result will be a DSB with partially complementary 3 0 or 5 0 overhangs and a one-base gap in each strand.…”

Section: End-joining Of Free Radical-mediated Double-strand Breaksmentioning

confidence: 99%

Regulation and mechanisms of mammalian double-strand break repair

2003

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The double-strand break (DSB) is believed to be one of the most severe types of DNA damage, and if left unrepaired is lethal to the cell. Several different types of repair act on the DSB. The most important in mammalian cells are nonhomologous end-joining (NHEJ) and homologous recombination repair (HRR). NHEJ is the predominant type of DSB repair in mammalian cells, as opposed to lower eucaryotes, but HRR has recently been implicated in critical cell signaling and regulatory functions that are essential for cell viability. Whereas NHEJ repair appears constitutive, HRR is regulated by the cell cycle and inducible signal transduction pathways. More is known about the molecular details of NHEJ than HRR in mammalian cells. This review focuses on the mechanisms and regulation of DSB repair in mammalian cells, the signaling pathways that regulate these processes and the potential crosstalk between NHEJ and HRR, and between repair and other stress-induced pathways with emphasis on the regulatory circuitry associated with the ataxia telangiectasia mutated (ATM) protein.

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“…AP sites are considered to be both cytotoxic and mutagenic, and they have been estimated to occur spontaneously at a rate of approximately 104 cell-' day-' from the mammalian cell genome (Loeb et al, 1986). Reactive oxygen species generated either during normal cellular metabolism or by exogenous agents, such as ionizing radiation, can increase this high error rate still further (Hutchinson, 1985;Teoule, 1987).There are specific DNA repair enzymes that recognize AP sites. The major human AP endonuclease (HAPI), also known as APE, APEX or Ref-1, is a 37-kDa protein that shows strong primary sequence similarity to Escherichia coli exonuclease III protein (Demple et al, 1991;Seki et al, 1991; Correspondence to: AL Harris residue is subsequently removed by a phosphodiesterase, followed by filling in of the nucleotide gap by DNA polymerase and DNA ligase, which seals the nick and permits the accurate progress of a DNA replication fork.…”

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confidence: 99%

mentioning

confidence: 99%

Human AP endonuclease 1 (HAP1) protein expression in breast cancer correlates with lymph node status and angiogenesis

Kakolyris

Kaklamanis²,

Engels³

et al. 1998

Br J Cancer

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Summary Human AP endonuclease (HAP1) plays a major role in the repair of apurinic/apyrimidinic (AP) sites in cellular DNA. We used immunohistochemistry to examine the expression of HAP1 in normal breast and in 102 primary breast carcinomas. In normal breast epithelium, HAP1 had a uniformly nuclear localization. However, in lactating glandular epithelium, the expression of HAP1 was predominantly cytoplasmic. In carcinomas, both nuclear and cytoplasmic (44%), cytoplasmic (28%) or nuclear staining (24%) were observed. In four cases (4%), no HAP1 expression was detected. All patterns of expression for HAP1 were demonstrated for ductal carcinomas in situ (DCIS), although comedo-type DCIS were usually accompanied by mostly cytoplasmic staining. Similarly, the HAP1 expression in regions of invasive tumour necrosis was cytoplasmic. Pure nuclear HAP1 expression was significantly correlated with low angiogenesis (P = 0.007) and negative lymph node status (P = 0.001). In contrast, cases with cytoplasmic as well as nuclear staining were associated with poor prognostic factors, such as high angiogenesis (P = 0.03) and node positivity (P = 0.03). The pure nuclear staining may be related to better differentiation, as in normal breast, and hence better prognostic features, and cytoplasmic staining to a more metabolically active phenotype with high protein synthesis, as in lactating breast.Keywords: HAP1; breast cancer; immunohistochemistry; DNA repairThe DNA of all organisms, although inherently stable, is under constant threat from both endogenous and exogenous factors. The DNA repair process is of fundamental importance for the survival of all species, and recent studies have established the association of defective DNA repair machinery and cancer (Fishel et al, 1993;Leach et al, 1993).One of the most common lesions that arise in cellular DNA is the apurinic/apyrimidinic (AP) site, which results from the hydrolysis of the N-glycosyl bond linking the base to the deoxyribose moiety. AP sites are considered to be both cytotoxic and mutagenic, and they have been estimated to occur spontaneously at a rate of approximately 104 cell-' day-' from the mammalian cell genome (Loeb et al, 1986). Reactive oxygen species generated either during normal cellular metabolism or by exogenous agents, such as ionizing radiation, can increase this high error rate still further (Hutchinson, 1985;Teoule, 1987).There are specific DNA repair enzymes that recognize AP sites. The major human AP endonuclease (HAPI), also known as APE, APEX or Ref-1, is a 37-kDa protein that shows strong primary sequence similarity to Escherichia coli exonuclease III protein (Demple et al, 1991;Seki et al, 1991; Correspondence to: AL Harris residue is subsequently removed by a phosphodiesterase, followed by filling in of the nucleotide gap by DNA polymerase and DNA ligase, which seals the nick and permits the accurate progress of a DNA replication fork.Apart from its identification as a DNA repair protein, HAPI has been shown to regulate the reductive activation of oxidiz...

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Chemical Changes Induced in DNA by Ionizing Radiation

Cited by 541 publications

References 126 publications

Inactivation of the cyclin-dependent kinase inhibitor p15INK4b by deletion and de novo methylation with independence of p16INK4a alterations in murine primary T-cell lymphomas

Inactivation of the cyclin-dependent kinase inhibitor p15INK4b by deletion and de novo methylation with independence of p16INK4a alterations in murine primary T-cell lymphomas

Regulation and mechanisms of mammalian double-strand break repair

Human AP endonuclease 1 (HAP1) protein expression in breast cancer correlates with lymph node status and angiogenesis

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