Interplay of DNA damage and cell cycle signaling at the level of human replication protein A

Borgstahl, Gloria E. O.; Brader, Kerry; Mosel, Adam; Liu, Shengqin; Kremmer, Elisabeth; Goettsch, Kaitlin; Kolar, Carol; Nasheuer, Heinz-Peter; Oakley, Gregory G.

doi:10.1016/j.dnarep.2014.05.005

Cited by 19 publications

(18 citation statements)

References 68 publications

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“…DSB can be repaired by the two major pathways: non-homologous end joining (NHEJ) and homologous recombination repair (HRR) (27). DNA damage activates ATM through auto-phosphorylation and the activated ATM is thought to be the main regulator of HRR (16). DNA DSB can be induced after exposure to irradiation.…”

Section: Discussionmentioning

confidence: 99%

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MicroRNA-18a enhances the radiosensitivity of cervical cancer cells by promoting radiation-induced apoptosis

Pan

Yang

et al. 2015

Oncology Reports

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Abstract. Evidence has demonstrated that microRNAs (miRNAs) are important in the regulation of cellular radiosensitivity of various types of human cancer. The aim of this study was to examine the role of miR-18a in regulating the radiosensitivity of cervical cancer, in order to understand the underlying mechanism and to assess the potential of miR-18a as a biomarker for predicting radiosensitivity. The expression of miR-18a was investigated in 48 cervical cancer patients. The results revealed that miR-18a expression was significantly higher in radiosensitive patients than in radioresistant patients by RT-qPCR (P<0.05). Transient transfection experiments showed that miR-18a was upregulated by the miR-18a mimic and downregulated by the miR-18a inhibitor in the SiHa and HeLa cells. Without irradiation treatment, a similar growth was observed in the cells with or without transfection of miR-18a. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and Hoechst staining assays showed that miR-18a had no effect on the proliferation and apoptosis of cervical cancer cells after transfection. However, the upregulation of miR-18a suppressed the level of ataxia-telangiectasia mutated and attenuated DNA double-strand break repair after irradiation, which re-sensitized the cervical cancer cells to radiotherapy by promoting apoptosis. Taken together, these results demonstrated that miR-18a is a potential molecule predictor of radiosensitivity in cervical cancer patients and played an important role in the response to radiotherapy.

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Section: Discussionmentioning

confidence: 99%

“…When cells respond to DNA damage, the initial step is the phosphorylation of repair proteins, such as the ATM and H2AX (11,16,17). If the ATM decreases, the DSB repair signaling pathway is impaired and cell apoptosis is enhanced.…”

Section: Overexpression Of Mir-18a Impairs the Double-strand Break (Dmentioning

confidence: 99%

MicroRNA-18a enhances the radiosensitivity of cervical cancer cells by promoting radiation-induced apoptosis

Pan

Yang

et al. 2015

Oncology Reports

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“…Escherichia coli RecG and T4 UvsW are regulated by interactions with their SSBs (15,21,22). Furthermore, RPA regulates the specificity of many other reactions during replication and repair while being rapidly placed on and taken off DNA (17,23,24). The mechanisms underlying this fundamental aspect of DNA biology remain largely unknown.…”

mentioning

confidence: 99%

High-affinity DNA-binding Domains of Replication Protein A (RPA) Direct SMARCAL1-dependent Replication Fork Remodeling

Bhat

Bétous

Chen

2015

Journal of Biological Chemistry

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Background: Replication protein A (RPA) inhibits SMARCAL1 translocation on some substrates but activates it on others. Results: High-affinity RPA DNA-binding domains (DBDs) are critical to confer substrate specificity to SMARCAL1. Conclusion: The orientation of the RPA DBDs at the replication fork controls SMARCAL1 substrate specificity. Significance: The results provide insight into the regulation of DNA translocases by ssDNA-binding proteins.

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“…In yeast cells, only phosphorylation of S4/S8 and S12 appear to depend on DNA damage. Recently, it was shown that human cells in G2 display chromatin-bound Rpa2 that is phosphorylated on S33 in the absence of DNA damaging agent and is increased upon damage induction (51). Yeast cells that are grown exponentially are predominantly in G2/M phase, and this could explain the apparent phosphorylation of S33 on Rfa2-h2NT in undamaged cells.…”

Section: Discussionmentioning

confidence: 99%

“…The other major difference lies in modification of T21, which in yeast cells appears to be phosphorylated in both unstressed and stressed cells. Phosphorylation of T21 is one of the first residues to be phosphorylated in a damage-specific manner in human cells (51) and appears to be important for priming phosphorylation of other sites (17). It is possible that low levels of damage that occur naturally in exponentially growing yeast cells are enough to trigger phosphorylation of T21 in the absence of damage induction.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation and cellular function of the human Rpa2 N-terminus in the budding yeast Saccharomyces cerevisiae

Ghospurkar

Wilson

Liu

et al. 2015

Experimental Cell Research

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Maintenance of genome integrity is critical for proper cell growth. This occurs through accurate DNA replication and repair of DNA lesions. A key factor involved in both DNA replication and the DNA damage response is the heterotrimeric single-stranded DNA (ssDNA) binding complex Replication Protein A (RPA). Although the RPA complex appears to be structurally conserved throughout eukaryotes, the primary amino acid sequence of each subunit can vary considerably. Examination of sequence differences along with the functional interchangeability of orthologous RPA subunits or regions could provide insight into important regions and their functions. This might also allow for study in simpler systems. We determined that substitution of yeast Replication Factor A (RFA) with human RPA does not support yeast cell viability. Exchange of a single yeast RFA subunit with the corresponding human RPA subunit does not function due to lack of inter-species subunit interactions. Substitution of yeast Rfa2 with domains/regions of human Rpa2 important for Rpa2 function (i.e., the N-terminus and the loop 3–4 region) supports viability in yeast cells, and hybrid proteins containing human Rpa2 N-terminal phospho-mutations result in similar DNA damage phenotypes to analogous yeast Rfa2 N-terminal phospho-mutants. Finally, the human Rpa2 N-terminus (NT) fused to yeast Rfa2 is phosphorylated in a manner similar to human Rpa2 in human cells, indicating that conserved kinases recognize the human domain in yeast. The implication is that budding yeast represents a potential model system for studying not only human Rpa2 N-terminal phosphorylation, but also phosphorylation of Rpa2 N-termini from other eukaryotic organisms.

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Interplay of DNA damage and cell cycle signaling at the level of human replication protein A

Cited by 19 publications

References 68 publications

MicroRNA-18a enhances the radiosensitivity of cervical cancer cells by promoting radiation-induced apoptosis

MicroRNA-18a enhances the radiosensitivity of cervical cancer cells by promoting radiation-induced apoptosis

High-affinity DNA-binding Domains of Replication Protein A (RPA) Direct SMARCAL1-dependent Replication Fork Remodeling

Phosphorylation and cellular function of the human Rpa2 N-terminus in the budding yeast Saccharomyces cerevisiae

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