Mitotic crisis: The unmasking of a novel role for RPA

Anantha, Rachel William; Borowiec, James A.

doi:10.4161/cc.8.3.7496

Cited by 30 publications

(24 citation statements)

References 51 publications

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“…These stalled replication structures are subsequently repaired by error-prone pathways, leading to loss and gain of DNA from chromosomal DNA regions and thereby generating the distribution of G1 cells we observe by FACS. Alternatively, recent work by our laboratory found a role for RPA phosphorylation in stimulating cellular transit through a damaged mitosis (Anantha and Borowiec, 2009;Anantha et al, 2008). We found that mitotic DNA damage in cells replaced with an RPA2 phosphorylation mutant (i.e.…”

Section: Discussionmentioning

confidence: 67%

“…Because these mutant factors are competent to bind to sites of DNA damage, it has been argued that hyperphosphorylation inhibits RPA loading onto ssDNA by the replication machinery (Vassin et al, 2004). Mitotic RPA2 hyperphosphorylation in response to mitotic DNA damage facilitates release of cells into G1 and increases cell viability, apparently by a signaling mechanism (Anantha and Borowiec, 2009;Anantha et al, 2008). In response to genotoxic stress, it was shown that cells expressing an RPA2 variant that was mutated at both Cdk2 sites (S23 and S29) had aberrant RPA foci and increased persistence of the DNA-damage marker H2AX following genotoxic stress (Anantha et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Human RPA phosphorylation by ATR stimulates DNA synthesis and prevents ssDNA accumulation during DNA-replication stress

Vassin

Anantha

Sokolova

et al. 2009

Journal of Cell Science

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167

149

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under non-stress conditions, the mutant cells were severely deficient in the amount of DNA synthesis occurring during replication stress. These cells also had abnormally high levels of chromatin-bound RPA, indicative of increased amounts of single-stranded DNA (ssDNA) and showed defective recovery from stress. Cells replaced with the mutant RPA2 also generated G1 cells with a broader DNA distribution and high levels of apoptosis following stress, compared with cells expressing wild-type RPA2. Surprisingly, cells expressing the wild-type RPA2 subunit had increased levels of stress-dependent DNA breaks. Our data demonstrate that RPA phosphorylation at the T21 and S33 sites facilitates adaptation of a DNA-replication fork to replication stress. Supplementary material available online at

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Section: Discussionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Human RPA phosphorylation by ATR stimulates DNA synthesis and prevents ssDNA accumulation during DNA-replication stress

Vassin

Anantha

Sokolova

et al. 2009

Journal of Cell Science

Self Cite

167

149

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“…RPA is essential for homologous recombination repair of double-stranded DNA breaks and plays a supporting role in nonhomologous end joining (119). XPA interacts with RPA, and both proteins transmit DNA damage signals to cell cycle checkpoints: XPA to the G 2 /M checkpoint and RPA to the spindle assembly checkpoint (2,64). RPA1 also has a critical role in telomere length maintenance (51).…”

Section: Methodsmentioning

confidence: 99%

A Protein Array Screen for Kaposi's Sarcoma-Associated Herpesvirus LANA Interactors Links LANA to TIP60, PP2A Activity, and Telomere Shortening

Shamay

Liu

et al. 2012

J Virol

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The Kaposi's sarcoma-associated herpesvirus (KSHV) LANA protein functions in latently infected cells as an essential participant in KSHV genome replication and as a driver of dysregulated cell growth. To identify novel LANA protein-cell protein interactions that could contribute to these activities, we performed a proteomic screen in which purified, adenovirus-expressed Flag-LANA protein was incubated with an array displaying 4,192 nonredundant human proteins. Sixty-one interacting cell proteins were consistently detected. LANA interactions with high-mobility group AT-hook 1 (HMGA1), HMGB1, telomeric repeat binding factor 1 (TRF1), xeroderma pigmentosum complementation group A (XPA), pygopus homolog 2 (PYGO2), protein phosphatase 2A (PP2A)B subunit, Tat-interactive protein 60 (TIP60), replication protein A1 (RPA1), and RPA2 proteins were confirmed in coimmunoprecipitation assays. LANA-associated TIP60 retained acetyltransferase activity and, unlike human papillomavirus E6 and HIV-1 TAT proteins, LANA did not reduce TIP60 stability. The LANA-bound PP2A B subunit was associated with the PP2A A subunit but not the catalytic C subunit, suggesting a disruption of PP2A phosphatase activity. This is reminiscent of the role of simian virus 40 (SV40) small t antigen. Chromatin immunoprecipitation (ChIP) assays showed binding of RPA1 and RPA2 to the KSHV terminal repeats. Interestingly, LANA expression ablated RPA1 and RPA2 binding to the cell telomeric repeats. In U2OS cells that rely on the alternative mechanism for telomere maintenance, LANA expression had minimal effect on telomere length. However, LANA expression in telomerase immortalized endothelial cells resulted in telomere shortening. In KSHV-infected cells, telomere shortening may be one more mechanism by which LANA contributes to the development of malignancy.

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“…It has also been reported to interact with, BRCA1 and BRCA2, which are 2 breast cancer susceptibility proteins potentially involved in recombination, as well as tumor suppressor p53 [15,16,17]. Moreover, RPA has been found to act as a key sensor to elicit DNA damage response after cellular exposure to genotoxic stresses and more recently identified as a key mediator of mitotic crisis [18,19]. Since p53 is dysregulated in HCC, it is likely that RPA3 promotes HCC tumorigenesis via perturbation of the p53 function.…”

Section: Discussionmentioning

confidence: 99%

Replication Protein A 3 Is Associated with Hepatocellular Carcinoma Tumorigenesis and Poor Patient Survival

Xiao

Zheng²,

Zhou³

et al. 2017

Dig Dis

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Background: Replication protein A (RPA) 3 is a subunit of the RPA protein complex, which functions in multiple processes of DNA metabolism. Dysregulation of RPA1 and RPA2 has been implicated in tumor progression in several cancer types. However, the function of RPA3 in hepatocellular carcinoma (HCC) tumorigenesis has not been elucidated. Method: In this study, we investigated the function of RPA3 in HCC development by stably knocking down its expression using short hairpin RNA (shRNA) in HepG2 cell line, followed by cell proliferation, colony formation, soft agar, and invasion assays. Xenograft experiment was performed to examine in vivo tumor-promoting properties of RPA3. Results: Downregulation of RPA3-inhibited cell proliferation, colony formation, soft agar growth as well as invasion in HepG2 cells were observed. Stable knockdown of RPA3 significantly inhibited tumor growth in the xenograft mouse model. In addition, qRT-PCR analysis revealed that RPA3 was upregulated in human HCC tissues compared with matched noncancerous adjacent tissues (NATs). High expression of RPA3 was associated with poor overall survival and disease-free survival. Conclusion: Elevated expression of RPA3 promotes tumor progression in HCC cells. RPA3 is upregulated in HCC tissues and high expression of RPA3 is associated with poorer patient survival. Therefore, this protein may represent a novel therapeutic target for intervention of HCC and prognostic biomarker for patient survival.

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Mitotic crisis: The unmasking of a novel role for RPA

Cited by 30 publications

References 51 publications

Human RPA phosphorylation by ATR stimulates DNA synthesis and prevents ssDNA accumulation during DNA-replication stress

Human RPA phosphorylation by ATR stimulates DNA synthesis and prevents ssDNA accumulation during DNA-replication stress

A Protein Array Screen for Kaposi's Sarcoma-Associated Herpesvirus LANA Interactors Links LANA to TIP60, PP2A Activity, and Telomere Shortening

Replication Protein A 3 Is Associated with Hepatocellular Carcinoma Tumorigenesis and Poor Patient Survival

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