Duplicated region of sequence similarity to the human<i>XRCC1</i>DNA repair gene in the Schizosaccharomyces pombe<i>rad4/cut5</i>gene

Lehmann, Alan R.

doi:10.1093/nar/21.22.5274

Cited by 19 publications

(9 citation statements)

References 5 publications

(4 reference statements)

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“…These results indicate that the central portion of XRCC1 is involved in binding to PARP and suggest that amino acids within the region of residues 301 to 402 are required for the interaction. Interestingly, this domain is homologous to a duplicated sequence in the Schizosaccharomyces pombe rad4/cut5 gene (29), which is required for maintaining the dependency of mitosis on correct progression through the cell cycle (40). As is clearly visible in Fig.…”

Section: Xrcc1 Interacts With Parp By Its Domain Homologous Tomentioning

confidence: 90%

XRCC1 Is Specifically Associated with Poly(ADP-Ribose) Polymerase and Negatively Regulates Its Activity following DNA Damage

Masson

Niedergang

Schreiber

et al. 1998

Molecular and Cellular Biology

846

611

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Poly(ADP-ribose) polymerase (PARP; EC 2.4.2.30) is a zinc-finger DNA-binding protein that detects and signals DNA strand breaks generated directly or indirectly by genotoxic agents. In response to these breaks, the immediate poly(ADP-ribosyl)ation of nuclear proteins involved in chromatin architecture and DNA metabolism converts DNA damage into intracellular signals that can activate DNA repair programs or cell death options. To have greater insight into the physiological function of this enzyme, we have used the two-hybrid system to find genes encoding proteins putatively interacting with PARP. We have identified a physical association between PARP and the base excision repair (BER) protein XRCC1 (X-ray repair cross-complementing 1) in the Saccharomyces cerevisiae system, which was further confirmed to exist in mammalian cells. XRCC1 interacts with PARP by its central region (amino acids 301 to 402), which contains a BRCT (BRCA1 C terminus) module, a widespread motif in DNA repair and DNA damage-responsive cell cycle checkpoint proteins. Overexpression of XRCC1 in Cos-7 or HeLa cells dramatically decreases PARP activity in vivo, reinforcing the potential protective function of PARP at DNA breaks. Given that XRCC1 is also associated with DNA ligase III via a second BRCT module and with DNA polymerase ␤, our results provide strong evidence that PARP is a member of a BER multiprotein complex involved in the detection of DNA interruptions and possibly in the recruitment of XRCC1 and its partners for efficient processing of these breaks in a coordinated manner. The modular organizations of these interactors, associated with small conserved domains, may contribute to increasing the efficiency of the overall pathway.The genomic integrity of cells is controlled by a network of protein factors that assess the status of the genome and either cause progression of proliferation or induce a halt in the cell cycle. In eukaryotes, DNA strand breaks, introduced either directly by ionizing radiation or indirectly following enzymatic incision of a DNA lesion, trigger the synthesis of poly(ADPribose) by the enzyme poly(ADP-ribose) polymerase (PARP) (1,13,39). At the site of breakage, PARP catalyzes the transfer of the ADP-ribose moiety from its substrate, NAD ϩ , to a limited number of protein acceptors involved in chromatin architecture and DNA metabolism, including the enzyme itself. These modified proteins, which carry long chains of negatively charged ADP-ribose polymers, lose their affinity for DNA and are thus inactivated. The short half-life of the polymer is attributed to the high activity of poly(ADP-ribose) glycohydrolase, which cleaves the ribose-ribose bond (28, 30). Therefore, poly(ADP-ribosylation) is an immediate but transient postranslational modification of nuclear proteins, induced by DNA-damaging agents.The physiological role of PARP has been much debated in the last decade, but recent molecular and genetic approaches, including expression of either a dominant-negative mutant (26,36,44) or antisense oligonucleo...

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Section: Xrcc1 Interacts With Parp By Its Domain Homologous Tomentioning

confidence: 90%

XRCC1 Is Specifically Associated with Poly(ADP-Ribose) Polymerase and Negatively Regulates Its Activity following DNA Damage

Masson

Niedergang

Schreiber

et al. 1998

Molecular and Cellular Biology

846

611

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“…Rad4 is identical to CutS, which is required for the onset of S phase and for the restraint of M phase before the completion of S phase [ 141. While the region 1 of XRCCI that contains the amino acid sequence THLI is reported to be duplicated in the regions of Rad4 [19], TopBPl possesses eight similar regions (Fig. 3).…”

Section: Discussionmentioning

confidence: 99%

A DNA‐Topoisomerase‐11–Binding Protein with Eight Repeating Regions Similar to DNA‐repair Enzymes and to a Cell‐Cycle Regulator

Yamane

Kawabata

Tsuruo

1997

European Journal of Biochemistry

105

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A two-hybrid system was used to isolate factors that interact with the C-terminal region of DNA topoisomerase IIP. A positive clone isolated from a HeLa cDNA library encoded 1.522 amino acid residues (molecular mass 170670). The protein, designated topoisomerase-ITP-binding protein 1 (TopBPl), interacted with the C-terminal region of topoisomerase IIP synthesized in vitw. A database search indicated that TopBPl possessed eight regions similar to regions of Rad4, Cut.5, Ect2, Revl and X-ray repair cross-complementing 1 (XRCC1) proteins and a region similar to auto-modification sites of poly(ADPribose) polymerase, suggesting that TopBPl supported catalytic reactions of topoisomerase I1 through transient breakages of DNA strands. . Therefore, a decrease in the number of cleavable complexes, including a reduction in enzyme quantity and activity, could confer drug resistance. Solid tumors that are naturally under stress conditions (e.g. hypoxia and glucose starvation) show a low amount of topoisomerase 11, which suggests that the resistance of solid tumors to chemotherapy is partly due to the decreased amount of topoisomerase I1 as the molecular target of major antitumor reagents [6, 71. To identify the factors involved in the regulatory mechanisms of topoisomerase I1 and to investigate the resistance mechanisms of solid tumors to chemotherapy, we adopted a twohybrid system [S], using the C-terminal region of human topoisomerase IIP. An isolated clone encoded eight repeating regions that are similar to the regions of Rad4, Cuts, Revl and X-ray repair cross-complementing (XRCC1) proteins, which are involved in DNA repair or regulation of the cell cycle. The protein, designated topoisomerase-binding protein 1 (TopBPl) contained a region similar to automodification sites of poly(ADPribose) polymerase, and may be involved in cell-cycle regulation and DNA repair, caused by failure of catalytic reactions of topoisomerase IT through DNA strand breaks. Keywords MATERIALS AND METHODSPlasmid construction. The C-terminal region of the human topoisomerase IlP gene [2] was amplified by PCR. The templates were cDNAs prepared from human kidney (Clontech, Quick-clone). Oligonucleotides used were 5'-GGATCCGGT-CAAAGAAAGATTTGAT-TCAAATG-3' and 5'-GATTTGTT-GAAAAATGTTTGTGCTC-3'. The region corresponding to amino acid 1143-1621 of topoisomerase Ilg was cloned into the BumH1-XhoI site of pEG202 [S], carrying the Zed gene to construct pK83.5 (a bait plasmid).Yeast two-hybrid system. The system was a kind gift of Dr Roger Brent, Harvard Medical School. Screening was performed according to his procedures [S]. Saccharumyces cer-evi.r.iue, ECY48 was transformed with pSH18-34 (a reporter) and pK83.5 (a bait). A HeLa cDNA expression library 181 was introduced into the transformants. After 2 days, approximately 10' independent clones which contained pSH18-34, pK835 and a cDNA plasmid, were replicated onto plates that lacked leucine but contained 5-broino-4-chloro-3-~ndoyl-~-~-galactopyranos~de and Dgalactose. A positive cDNA clone (termed pK835-5...

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“…However, temperature-sensitive cdcl8 mutant cells are arrested in G2 phase. The expression of both genes is cell cycle-regulated in a manner dependent on the cdcJO+ gene, the product of which is a transcriptional activator at START: the 5' region upstream of the genes contains the MluI motif known to be the binding site for the transcription factor DSClsp, of which the cdclO protein is a component (Lowndes et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

Fission yeast cut5 links nuclear chromatin and M phase regulator in the replication checkpoint control.

et al. 1994

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Fission yeast temperature‐sensitive cut5 (cell untimely torn) mutants are defective in initiation and/or elongation of DNA replication but allow mitosis and cell division at a restrictive temperature. We show that the cut5 protein (identical to rad4) (i) is an essential component of the replication checkpoint system but not the DNA damage checkpoint, and (ii) negatively regulates the activation of M phase kinase at mitotic entry. Even if the replication checkpoint has been activated previously, cut5 mutations allow mitosis and cell division after shift to 36 degrees C. Transcription of cut5+ is not under the control of the START gene cdc10+. The cut5 protein is enriched in the nucleus, consisting of repeating domains. An essential domain which resembles the proto‐oncoprotein Ect2 has a strong negative effect on the entry into mitosis when overexpressed. Expression of the cut5 mutant phenotype requires the function of the M phase regulator genes cdc2+, cdc25+ and cdc13+. The cut5 protein forms a novel, essential link between DNA synthesis and M phase activation in the replication checkpoint control pathway.

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Duplicated region of sequence similarity to the humanXRCC1DNA repair gene in the Schizosaccharomyces pomberad4/cut5gene

Cited by 19 publications

References 5 publications

XRCC1 Is Specifically Associated with Poly(ADP-Ribose) Polymerase and Negatively Regulates Its Activity following DNA Damage

XRCC1 Is Specifically Associated with Poly(ADP-Ribose) Polymerase and Negatively Regulates Its Activity following DNA Damage

A DNA‐Topoisomerase‐11–Binding Protein with Eight Repeating Regions Similar to DNA‐repair Enzymes and to a Cell‐Cycle Regulator

Fission yeast cut5 links nuclear chromatin and M phase regulator in the replication checkpoint control.

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