RPA involvement in the damage-recognition and incision steps of nucleotide excision repair

He, Zhigang; Henricksen, Leigh A.; Wold, Marc S.; Ingles, C J

doi:10.1038/374566a0

Cited by 389 publications

(346 citation statements)

References 29 publications

Supporting

Mentioning

327

Contrasting

Unclassified

Order By: Relevance

“…RPA is a highly conserved, single-stranded DNA-binding multisubunit protein complex involved in eukaryotic DNA replication, recombination and repair. 3,5 Previous experimental studies in colon cancer cell lines have reported a reduction in DNA replication activity in parallel with the reduction of RPA1 protein suggesting a crucial role of RPA complex for the proliferative activity of colon cancer cells. 14 However, there is no previous study investigating the in vivo expression of RPA proteins in human colon cancer tissues.…”

Section: Discussionmentioning

confidence: 97%

See 1 more Smart Citation

Replication protein A is an independent prognostic indicator with potential therapeutic implications in colon cancer

et al. 2007

View full text Add to dashboard Cite

Replication protein A (RPA), a component of the origin recognition complex, is required for stabilization of single-stranded DNA at early and later stages of DNA replication being thus critical for eukaryotic DNA replication. Experimental studies in colon cancer cell lines have shown that RPA protein may be the target of cytotoxins designed to inhibit cellular proliferation. This is the first study to investigate the expression of RPA1 and RPA2 subunits of RPA protein and assess their prognostic value in colon cancer patients. We analyzed immunohistochemically the expression of RPA1 and RPA2 proteins in a series of 130 colon cancer resection specimens in relation to conventional clinicopathological parameters and patients' survival. Statistical significant positive associations emerged between: (a) RPA1 and RPA2 protein expressions (P ¼ 0.0001), (b) RPA1 and RPA2 labelling indices (LIs) and advanced stage of the disease (P ¼ 0.001 and 0.003, respectively), (c) RPA1 and RPA2 LIs and the presence of lymph node metastasis (P ¼ 0.002 and 0.004, respectively), (d) RPA1 LI and the number of infiltrated lymph nodes (P ¼ 0.021), (e) RPA2 LI and histological grade of carcinomas (P ¼ 0.05). Moreover, a statistical significant higher RPA1 LI was observed in the metastatic sites compared to the original ones (P ¼ 0.012). RPA1 and RPA2 protein expression associated with adverse patients' outcome in both univariate (log rank test: Po0.00001 and 0.00001, respectively) and multivariate (Cox model: P ¼ 0.092 and 0.0001, respectively) statistical analysis. Statistical significant differences according to the expression of RPA1 and RPA2 proteins were also noticed in the survival of stage II (Po0.00001 and 0.0016, respectively) and stage III (P ¼ 0.0029 and 0.0079, respectively) patients. In conclusion, RPA1 and RPA2 proteins appear to be useful prognostic indicators in colon cancer patients and attractive therapeutic targets for regulation by tumor suppressors or other proteins involved in the control of cell proliferation. Modern Pathology (2007) 20, 159-166.

show abstract

Section: Discussionmentioning

confidence: 97%

“…3,4 Moreover, RPA is involved in DNA recombination and repair. [5][6][7][8] Additionally, it has also been implicated in the regulation of apoptosis and gene expression. 9 Links between RPA and transcription have been postulated based on the observed interactions between RPA and Gal4, VP16, p53, Stat3, RBT1 and menin.…”

mentioning

confidence: 99%

Replication protein A is an independent prognostic indicator with potential therapeutic implications in colon cancer

et al. 2007

View full text Add to dashboard Cite

show abstract

“…The binding of p53 with CSB is consistent with a role of p53 in damage recognition because CSB, together with CSA, are thought to ®rst recognize the stalled transcription complex (Hanawalt, 1994;Selby and Sancar, 1994;Drapkin et al, 1994b). Repair of damaged DNA could also be enhanced by the association of p53 with RPA, which, in complex with the XPA gene product (He et al, 1995), is believed to be recruited next to the site of the lesion (Hanawalt, 1994;Selby and Sancar, 1994;Drapkin et al, 1994). The TFIIH repairosome is thought to be targeted to the DNA at this point, probably through its association with XPA (Park et al, 1995).…”

Section: Discussionmentioning

confidence: 52%

p53-mediated transcription induces resistance of DNA to UV inactivation

et al. 1998

View full text Add to dashboard Cite

A possible role of p53-dependent transcription in the induction of DNA repair was explored by transfecting a UV-irradiated chloramphenicol acetyl transferase (CAT) reporter plasmid (pRGC.FOS.CAT), containing a minimal FOS promoter driven by a consensus p53 binding site, into a p53 negative-mouse cell line [(10)1]. When a p53-expressing plasmid (pSV.p53) was cotransfected into these cells, CAT expression levels persisted even after prolonged UV irradiation. In comparison, CAT expression from pSV2.CAT, which lacks a p53-responsive element in its SV40 promoter, dropped o much more precipitously after UV irradiation in the absence or presence of WT p53 expression. A similar sharp drop was observed with three other constructs when the reporter gene was under the control of the ras, b-actin or fos promoter. Mouse cells (A1-5) that constitutively express a temperature-sensitive mutant (135 AV) of mouse p53 also generated, at 328C, higher levels of enzyme expressed from UV-irradiated pRGC.FOS.CAT than from UV-irradiated pSV2.CAT. The frequency of cyclobutane pyrimidine dimers in UV-irradiated pRGC.FOS.CAT was determined with T4 endo V, and the probability of having an undamaged CAT coding strand was calculated by the Poisson distribution for various times of UV-irradiation. The observed relative CAT expression levels from irradiated pSV2.CAT and pRGC.FOS.CAT in the absence of p53 were consistent with those numbers. These results show that WT p53-mediated transcription directs a resistance of the transcribed DNA to UV inactivation and reactivates the reporter gene. Furthermore, some single point substitution mutants of p53 that maintain a near normal ability to activate transcription had lost their ability to extend CAT gene expression after UV irradiation. Conversely, other mutants with reduced transcriptional activity retained this ability. This indicates that although resistance to UV inactivation is transcriptionally-dependent, these two activities are genetically distinct. These data, taken together, suggest that the transcription of UV-damaged DNA by a p53-dependent process promotes its repair.

show abstract

“…RPA is involved in the early stage of NER by interacting with XPA on damaged DNA, which allows the stable RPA-XPA complex to form on damaged DNA [22][23][24][25]27]. Since the zincfinger mutant failed to support NER, we were interested in examining whether the mutation at the zinc-finger domain affects XPA-DNA interaction.…”

Section: Zinc-finger Domain Of Rpa Is Not Necessary For Its Stimulatomentioning

confidence: 99%

“…In nucleotide excision repair (NER), RPA forms a complex with Xeroderma pigmentosum group A complementing protein (XPA) [22][23][24][25], a protein that specifically recognizes UV damage [26]. RPA stimulates the interaction of XPA with DNA through an RPA-XPA complex at damaged DNA sites [23,24,27].…”

Section: Introductionmentioning

confidence: 99%

In vitro analysis of the zinc-finger motif in human replication protein A

Dong

Park

Lee

1999

Biochemical Journal

View full text Add to dashboard Cite

Human replication protein A (RPA) is composed of 70, 34 and 11 kDa subunits (p70, p34 and p11 respectively) and functions in all three major DNA metabolic processes : replication, repair and recombination. Recent deletion analysis demonstrated that the large subunit of RPA, p70, has multiple functional domains, including a DNA polymerase α-stimulation domain and a singlestranded DNA-binding domain. It also contains a putative metal-binding domain of the 4-cysteine type (Cys-Xaa % -CysXaa "$ -Cys-Xaa # -Cys) that is highly conserved among eukaryotes. To study the role of this domain in DNA metabolism, we created various p70 mutants that lack the zinc-finger motif (by Cys Ala substitutions). Mutation at the zinc-finger domain (ZFM) abolished RPA's function in nucleotide excision repair (NER), but had very little impact on DNA replication. The failure of

show abstract

RPA involvement in the damage-recognition and incision steps of nucleotide excision repair

Cited by 389 publications

References 29 publications

Replication protein A is an independent prognostic indicator with potential therapeutic implications in colon cancer

Replication protein A is an independent prognostic indicator with potential therapeutic implications in colon cancer

p53-mediated transcription induces resistance of DNA to UV inactivation

In vitro analysis of the zinc-finger motif in human replication protein A

Contact Info

Product

Resources

About