The DNA Helicase Recql4 Is Required for Normal Osteoblast Expansion and Osteosarcoma Formation

Ng, Alvin J. M.; Walia, Mannu; Smeets, Monique; Mutsaers, Anthony J.; Sims, Natalie A.; Purton, Louise E.; Walsh, Nicole C.; Martın, Thomas; Walkley, Carl R.

doi:10.1371/journal.pgen.1005160

Cited by 36 publications

(48 citation statements)

References 57 publications

(98 reference statements)

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“…Lu et al suggested that RECQL4 is critical for skeletal development by modulating p53 activity in vivo [83]. Ng et al further suggested that mutant, not null, alleles of RECQL4 may account for tumor suppression and susceptibility for OS [84]. These mouse data are indeed consistent with a previous proposal based on clinical studies, that there are two types of RTS: Type II, which presents OS features and Type I, which does not [81].…”

Section: Understanding the Role Of Driver Gene Mutations In The Desupporting

confidence: 80%

“…Complete loss of function of Recql4 in mice leads to embryonic death, which implies that the mutated RECQL4 gene in RTS patients may have enough residual activity to maintain cell survival [82]. In skeletal cells, complete loss of function of Recql4 leads to developmental bone abnormalities and adult osteoporosis, but does not induce the development of OS [83, 84]. Lu et al suggested that RECQL4 is critical for skeletal development by modulating p53 activity in vivo [83].…”

Section: Understanding the Role Of Driver Gene Mutations In The Dementioning

confidence: 99%

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Molecular genetics of osteosarcoma

Rickel

Fang

Tao

2017

Bone

194

179

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Osteosarcoma is the predominant form of bone cancer, affecting mostly adolescents. Recent progress made in molecular genetic studies of osteosarcoma has changed our view on the cause of the disease and ongoing therapeutic approaches for patients. As we draw closer to gaining more complete catalogues of candidate cancer driver genes in common forms of cancer, the landscape of somatic mutations in osteosarcoma is emerging from its first phase. In this review, we summarize recent whole genome and/or whole exome genomic studies, and then put these findings in the context of genetic hallmarks of somatic mutations and mutational processes in human osteosarcoma. One of the lessons learned here is that the extent of somatic mutations and complexity of the osteosarcoma genome are similar to that of common forms of adult cancer. Thus, a much higher number of samples than those currently obtained are needed to complete the catalogue of driver mutations in human osteosarcoma. In parallel, genetic studies in other species have revealed candidate driver genes and their roles in the genesis of osteosarcoma. This review also summarizes newly identified drivers in genetically engineered mouse models (GEMMs) and discusses our understanding of the impact of nature and number of drivers on tumor latency, subtypes, and metastatic potentials of osteosarcoma. It is becoming apparent that a synergistic team composed of three drivers (one ‘first driver’ and two ‘synergistic drivers’) may be required to generate an animal model that recapitulates aggressive osteosarcoma with a short latency. Finally, new cancer therapies are urgently needed to improve survival rate and quality of life for osteosarcoma patients. Several vulnerabilities in osteosarcoma are illustrated in this review to exemplify the opportunities for next generation molecularly targeted therapies. However, much work remains in order to complete our understanding of the somatic mutation basis of osteosarcoma, to develop reliable animal models of human disease, and to apply this information to guide new therapeutic approaches for reducing morbidity and mortality of this rare disease.

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Section: Understanding the Role Of Driver Gene Mutations In The Desupporting

confidence: 80%

Section: Understanding the Role Of Driver Gene Mutations In The Dementioning

confidence: 99%

Molecular genetics of osteosarcoma

Rickel

Fang

Tao

2017

Bone

194

179

View full text Add to dashboard Cite

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“…Normal cell survival depends on the cell cycle operating normally and is controlled by the precise mechanism of cell cycle regulators (22). Tumor growth is thought to arise from dysregulation of the cell cycle.…”

Section: Discussionmentioning

confidence: 99%

Gambogic acid inhibits the growth of ovarian cancer tumors by regulating p65 activity

Tang

Zhou

et al. 2016

Oncology Letters

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Abstract. Ovarian cancer patients often have poor prognosis, therefore, it is important to search for more effective therapeutic strategies to treat them. Gambogic acid (GA) exhibits an anti-tumor effect through various mechanisms, and has multiple targets in tumor cells. The present study aimed to elucidate the efficacy of GA in the treatment of ovarian cancer both in vivo and in vitro by analyzing its impact on cell survival and tumor growth through cell cycle and apoptosis analysis. GA inhibited the growth of ovarian cancer cells in a dose and time dependent manner, and arrested the cell cycle in ovarian cancer cells. Furthermore, GA increased caspase-3 and caspase-9 activity and inhibited RELA/NF-κB p65 (p65) DNA binding activity. Finally, GA suppressed tumor growth in vivo. Therefore, the current study suggests that GA inhibits the growth of ovarian cancer by regulating p65 activity, and may be developed as a novel therapeutic strategy to treat ovarian cancer.

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“…8). Together, our results hint at a possible role of the RPS3-RECQL4 interaction in regulating the DNA repair induced by similar genotoxic stresses (28,34).…”

Section: Resultsmentioning

confidence: 52%

“…The conserved RecQ type helicase domain of RECQL4 is important for DNA repair function and aging (35,36). Mutations in RTS patients (23) are particularly concentrated in this domain (34). Because the N-terminal Sld2-like domain is sufficient to partially rescue lethal replication defects (1, 2), RECQL4 helicase activity is likely to be more important for its DNA repair function.…”

Section: Discussionmentioning

confidence: 99%

Ribosomal Protein S3 Negatively Regulates Unwinding Activity of RecQ-like Helicase 4 through Their Physical Interaction

Patil

Hsieh

2017

Journal of Biological Chemistry

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Edited by Patrick SungHuman RecQ-like helicase 4 (RECQL4) plays crucial roles in replication initiation and DNA repair; however, the contextual regulation of its unwinding activity is not fully described. Mutations in RECQL4 have been linked to three diseases including Rothmund-Thomson syndrome, which is characterized by osteoskeletal deformities, photosensitivity, and increased osteosarcoma susceptibility. Understanding regulation of RECQL4 helicase activity by interaction partners will allow deciphering its role as an enzyme and a signaling cofactor in different cellular contexts. We became interested in studying the interaction of RECQL4 with ribosomal protein S3 (RPS3) because previous studies have shown that RPS3 activity is sometimes associated with phenotypes mimicking those of mutated RECQL4. RPS3 is a small ribosomal protein that also has extraribosomal functions, including apurnic-apyrimidinic endonuclease-like activity suggested to be important during DNA repair. Here, we report a functional and physical interaction between RPS3 and RECQL4 and show that this interaction may be enhanced during cellular stress. We show that RPS3 inhibits ATPase, DNA binding, and helicase activities of RECQL4 through their direct interaction. Further domain analysis shows that N-terminal 1-320 amino acids of RECQL4 directly interact with the C-terminal 94 -244 amino acids of RPS3 (C-RPS3). Biochemical analysis of C-RPS3 revealed that it comprises a standalone apurnic-apyrimidinic endonuclease-like domain. We used U2OS cells to show that oxidative stress and UV exposure could enhance the interaction between nuclear RPS3 and RECQL4. Regulation of RECQL4 biochemical activities by RPS3 along with nuclear interaction during UV and oxidative stress may serve to modulate active DNA repair.The RecQ class of helicases function at various stages of DNA metabolism. The presence of at least one homolog in each species evidences their crucial role in maintaining genomic stability. In humans, three of five RecQ helicases have been associated to different genetic disorders. WRN and BLM have been linked with Werner's syndrome and Bloom's syndrome, respectively, and RECQL4 has been linked with Rothmund-Thomson syndrome (RTS), 2 Baller-Gerald syndrome, and RAPADILINO syndrome. Of these, RECQL4 is unique on the basis of its domain structure and function. The N terminus of this protein represents the only human homolog of Saccharomyces cerevisiae essential replication initiation protein Sld2 (1, 2). The helicase domain is conserved across the RecQ class of helicases. Initial reports suggested RECQL4 lacked of helicase activity (3), but annealing, strand exchange and helicase activities of RECQL4 were later demonstrated (4 -7). Human RECQL4 was shown to unwind up to 22-bp double-stranded regions through its helicase activity (6, 7). ATPase and annealing activities of human RECQL4 have also been extensively studied (7,8). Robust helicase and annealing activities on substrates of various lengths have been reported for Drosophila melanogaster R...

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The DNA Helicase Recql4 Is Required for Normal Osteoblast Expansion and Osteosarcoma Formation

Cited by 36 publications

References 57 publications

Molecular genetics of osteosarcoma

Molecular genetics of osteosarcoma

Gambogic acid inhibits the growth of ovarian cancer tumors by regulating p65 activity

Ribosomal Protein S3 Negatively Regulates Unwinding Activity of RecQ-like Helicase 4 through Their Physical Interaction

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