RECQL4, the Protein Mutated in Rothmund-Thomson Syndrome, Functions in Telomere Maintenance

Ghosh, Avik; Rossi, Marie L.; Singh, Dharmendra Kumar; Dunn, Christopher; Ramamoorthy, Mahesh; Croteau, Deborah L.; Liu, Yie; Bohr, Vilhelm A.

doi:10.1074/jbc.m111.295063

Cited by 112 publications

(137 citation statements)

References 61 publications

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“…Additionally, Hrq1 functions in the repair of DNA inter-strand crosslinks (ICL) in the same pathway as the ICL repair nuclease Pso2 [8,9]. Telomere maintenance and ICL repair are likewise associated with human RecQ4 [10,11]. In vitro, Hrq1 and RecQ4 helicase activity is stimulated by poly(dT) and telomeric repeat ssDNA [8].…”

Section: Introductionmentioning

confidence: 99%

Saccharomyces cerevisiae Hrq1 helicase activity is affected by the sequence but not the length of single-stranded DNA

Rogers

Bochman

2017

Biochemical and Biophysical Research Communications

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a b s t r a c tMutations in the human RecQ4 DNA helicase are associated with three different diseases characterized by genomic instability. To gain insight into how RecQ4 dysfunction leads to these pathologies, several groups have used the Saccharomyces cerevisiae RecQ4 homolog Hrq1 as an experimental model. Hrq1 displays many of the same functions as RecQ4 in vivo and in vitro. However, there is some disagreement in the literature about the effects of single-stranded DNA (ssDNA) length on Hrq1 helicase activity and the ability of Hrq1 to anneal complementary ssDNA oligonucleotides into duplex DNA. Here, we present a side-by-side comparison of Hrq1 and RecQ4 helicase activity, demonstrating that in both cases, long random-sequence 3 0 ssDNA tails inhibit DNA unwinding in vitro in a length-dependent manner. This appears to be due to the formation of secondary structures in the random-sequence ssDNA because Hrq1 preferentially unwound poly(dT)-tailed forks independent of ssDNA length. Further, RecQ4 is capable of ssDNA strand annealing and annealing-dependent strand exchange, but Hrq1 lacks these activities. These results establish the importance of DNA sequence in Hrq1 helicase activity, and the absence of Hrq1 strand annealing activity explains the previously identified discrepancies between S. cerevisiae Hrq1 and human RecQ4.

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Section: Introductionmentioning

confidence: 99%

Saccharomyces cerevisiae Hrq1 helicase activity is affected by the sequence but not the length of single-stranded DNA

Rogers

Bochman

2017

Biochemical and Biophysical Research Communications

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“…1,2 RecQL4 is a conserved protein in higher eukaryotes showing 3 0 to 5 0 DNA helicase activity, 3 and mutations in this gene are associated with Rothmund-Thomson Syndrome, which leads to developmental abnormalities, signs of premature aging, and high incidences of osteosarcoma. 4 While RecQL4 was shown to be involved in the cellular response to DNA damage or oxidative stress 5 and telomere maintenance, 6 RecQL4 also plays essential roles in DNA replication. Unlike other RecQ family proteins, RecQL4 has a distinct N-terminus showing limited homology to Sld2 which is an essential initiation factor in yeast, 7 and this N-terminal domain of RecQL4 was shown to be essential for the initiation of DNA replication in vertebrates.…”

Section: Introductionmentioning

confidence: 99%

RecQL4 is required for the association of Mcm10 and Ctf4 with replication origins in human cells

Park

Cho

et al. 2015

Cell Cycle

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Though RecQL4 was shown to be essential for the initiation of DNA replication in mammalian cells, its role in initiation is poorly understood. Here, we show that RecQL4 is required for the origin binding of Mcm10 and Ctf4, and their physical interactions and association with replication origins are controlled by the concerted action of both CDK and DDK activities. Although RecQL4-dependent binding of Mcm10 and Ctf4 to chromatin can occur in the absence of pre-replicative complex, their association with replication origins requires the presence of the pre-replicative complex and CDK and DDK activities. Their association with replication origins and physical interactions are also targets of the DNA damage checkpoint pathways which prevent initiation of DNA replication at replication origins. Taken together, the RecQL4-dependent association of Mcm10 and Ctf4 with replication origins appears to be the first important step controlled by S phase promoting kinases and checkpoint pathways for the initiation of DNA replication in human cells.

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“…However, robust ATP-dependent helicase activity for human RECQL4 has not been demonstrated for substrates with double-stranded regions longer than 22 bp (3,(5)(6)(7)30). Typically demonstration of strand exchange activity has been reported for substrates with longer double-stranded regions in the presence of excess single-stranded traps.…”

Section: Resultsmentioning

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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RECQL4, the Protein Mutated in Rothmund-Thomson Syndrome, Functions in Telomere Maintenance

Cited by 112 publications

References 61 publications

Saccharomyces cerevisiae Hrq1 helicase activity is affected by the sequence but not the length of single-stranded DNA

Saccharomyces cerevisiae Hrq1 helicase activity is affected by the sequence but not the length of single-stranded DNA

RecQL4 is required for the association of Mcm10 and Ctf4 with replication origins in human cells

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

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