Xeroderma pigmentosum variant associated with multiple cancers

Kuwamoto, Kazue; Miyauchi-Hashimoto, Hiroko; Isei, Taiki; Horio, Takeshi

doi:10.1111/j.1600-0781.1999.tb00072.x

Cited by 10 publications

(5 citation statements)

References 26 publications

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“…The human homolog of Rad30, hRAD30, has recently been identified as the gene responsible for xeroderma pigmentosum (XP) variant (XP-V), a rare hereditary skin cancer predisposition syndrome (47,48). This result suggests that polymerase bypass synthesis is an important component of the cellular DNA repair and genome maintenance functions.…”

Section: Discussionmentioning

confidence: 99%

A Human REV7 Homolog That Interacts with the Polymerase ζ Catalytic Subunit hREV3 and the Spindle Assembly Checkpoint Protein hMAD2

Murakumo

Roth

Ishii

et al. 2000

Journal of Biological Chemistry

174

157

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Widespread alteration of the genomic DNA is a hallmark of tumors, and alteration of genes involved in DNA maintenance have been shown to contribute to the tumorigenic process. The DNA polymerase of Saccharomyces cerevisiae is required for error-prone repair following DNA damage and consists of a complex between three proteins, scRev1, scRev3, and scRev7. Here we describe a candidate human homolog of S. cerevisiae Rev7 (hREV7), which was identified in a yeast two-hybrid screen using the human homolog of S. cerevisiae Rev3 (hREV3). The hREV7 gene product displays 23% identity and 53% similarity with scREV7, as well as 23% identity and 54% similarity with the human mitotic checkpoint protein hMAD2. hREV7 is located on human chromosome 1p36 in a region of high loss of heterozygosity in human tumors, although no alterations of hREV3 or hREV7 were found in primary human tumors or human tumor cell lines. The interaction domain between hREV3 and hREV7 was determined and suggests that hREV7 probably functions with hREV3 in the human DNA polymerase complex. In addition, we have identified an interaction between hREV7 and hMAD2 but not hMAD1. While overexpression of hREV7 does not lead to cell cycle arrest, we entertain the possibility that it may act as an adapter between DNA repair and the spindle assembly checkpoint. DNA damage is induced by a variety of endogenous and exogenous factors (1). Such DNA alterations include reactive oxygen damage, deamination, loss of nucleotides, nucleotide modifications, and DNA strand breaks. DNA damage repair has evolved to cope with these environmental and mutageninduced DNA alteration and plays a central role in maintaining the genetic stability of the organism (2, 3).Extensive studies of bacterial and yeast systems have identified components of the DNA repair machinery. In the yeast Saccharomyces cerevisiae, pyrimidine dimers induced by UV radiation damage are corrected by the RAD3 excision repair, the RAD6 postreplication repair, and the RAD52 recombinational repair pathways (for a review see Ref. 4). Interestingly, the removal of UV damage by the RAD6 pathway occurs by both error-free and error-prone (mutagenic) mechanisms (5, 6). The mutagenic repair of UV damage has been shown to require the UV revertible genes, REV1, REV3, and REV7, a lesion bypass polymerase complex consisting of a deoxycytidyl-transferase (Rev1), a polymerase catalytic subunit (Rev3), and a polymerase accessory protein (Rev7) (for review see Refs. 7 and 8). This polymerase complex has been termed polymerase .

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Section: Discussionmentioning

confidence: 99%

A Human REV7 Homolog That Interacts with the Polymerase ζ Catalytic Subunit hREV3 and the Spindle Assembly Checkpoint Protein hMAD2

Murakumo

Roth

Ishii

et al. 2000

Journal of Biological Chemistry

174

157

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“…In humans, individuals expressing a severely truncated (and apparently inactive) pol are said to have the Xeroderma pigmentosum variant (XP-V) phenotype (Masutani et al 1999b;Johnson et al 1999aJohnson et al , 2000b. These patients exhibit sunlight sensitivity and a concomitant increased incidence of cancers (predominantly of the skin), and their cultured cells exhibit altered mutation spectra (Cleaver and Carter 1973;Wang et al 1993;Raha et al 1996;McGregor et al 1999;Kuwamoto et al 1999).…”

mentioning

confidence: 99%

polι, a remarkably error-prone human DNA polymerase

Tissier

McDonald²,

Frank³

et al. 2000

Genes Dev.

291

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The Saccharomyces cerevisiae RAD30 gene encodes DNA polymerase η. Humans possess two Rad30 homologs. One (RAD30A/POLH) has previously been characterized and shown to be defective in humans with the Xeroderma pigmentosum variant phenotype. Here, we report experiments demonstrating that the second human homolog (RAD30B), also encodes a novel DNA polymerase that we designate polι. polι, is a distributive enzyme that is highly error-prone when replicating undamaged DNA. At template G or C, the average error frequency was ∼1 × 10−2. Our studies revealed, however, a striking asymmetry in misincorporation frequency at template A and T. For example, template A was replicated with the greatest accuracy, with misincorporation of G, A, or C occurring with a frequency of ∼1 × 10−4 to 2 × 10−4. In dramatic contrast, most errors occurred at template T, where the misincorporation of G was, in fact, favored ∼3:1 over the correct nucleotide, A, and misincorporation of T occurred at a frequency of ∼6.7 × 10−1. These findings demonstrate that polι is one of the most error-prone eukaryotic polymerases reported to date and exhibits an unusual misincorporation spectrum in vitro.

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“…With XPV where there are high levels of skin cancer but little hypersensitivity to cell killing, levels of UVB-induced apoptosis in the two cultures were intermediate between XPA and wild type, although XPV postirradiation RNA synthesis has been shown to be normal (Itoh et al, 1996;Kuwamoto et al, 1999). In this instance a modest increase in apoptosis does not appear to be associated with defective transcription coupled repair.…”

Section: Discussionmentioning

confidence: 86%

Ultraviolet-B-Induced Apoptosis and Cytokine Release in Xeroderma Pigmentosum Keratinocytes

Petit-Frère

Capulas

Lowe

et al. 2000

Journal of Investigative Dermatology

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We have assessed the ability of xeroderma pigmentosum and normal keratinocytes grown out from skin biopsies to undergo apoptosis after irradiation with ultraviolet B. Keratinocytes have been studied from xeroderma pigmentosum complementation groups A (three biopsies), C (three biopsies), D (one biopsy), xeroderma pigmentosum variant (two biopsies), and Cockayne syndrome (one biopsy). The three xeroderma pigmentosum group A and the xeroderma pigmentosum group D samples were at least six times more sensitive than normal cells to ultraviolet B-induced apoptosis. The xeroderma pigmentosum variant samples showed intermediate susceptibility. Xeroderma pigmentosum group C samples proved heterogeneous: one showed high sensitivity to apoptosis, whereas two showed near normal susceptibility. The Cockayne syndrome sample showed the high susceptibility of xeroderma pigmentosum groups A and D only at a higher fluence. These results suggest that the relationships between repair deficiency, apoptosis, and susceptibility to skin cancer are not straightforward. Ultraviolet B-induced skin cancer is also thought to be due in part to ultraviolet B-induced impairment of immune responses. The release of the inflammatory cytokines interleukin-6 and tumor necrosis factor-alpha from cultured xeroderma pigmentosum keratinocytes tended to occur at lower fluences than in normals, but was less extensive, and was more readily inhibited at higher fluences of ultraviolet B.

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Xeroderma pigmentosum variant associated with multiple cancers

Cited by 10 publications

References 26 publications

A Human REV7 Homolog That Interacts with the Polymerase ζ Catalytic Subunit hREV3 and the Spindle Assembly Checkpoint Protein hMAD2

A Human REV7 Homolog That Interacts with the Polymerase ζ Catalytic Subunit hREV3 and the Spindle Assembly Checkpoint Protein hMAD2

polι, a remarkably error-prone human DNA polymerase

Ultraviolet-B-Induced Apoptosis and Cytokine Release in Xeroderma Pigmentosum Keratinocytes

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