Unique and important consequences of RECQ1 deficiency in mammalian cells

Sharma, Sudha; Brosh, Robert M.

doi:10.4161/cc.7.8.5707

Cited by 41 publications

(57 citation statements)

References 118 publications

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“…Moreover, biochemical studies have shown that RECQ1 and BLM display distinct substrate specificities, indicating that these helicases are likely to perform nonoverlapping functions (43). These results suggest an important-though as yet mechanistically ill-defined-role for RECQ1 in cell cycle progression and/or DNA repair (52).…”

mentioning

confidence: 79%

“…Cellular functions of RECQ1, in contrast to those of RECQ4, are not as well defined. We and others have shown that acute depletion of RECQ1 affects cellular proliferation (23,51,52). Moreover, RECQ1 depletion renders cells sensitive to DNA damage and leads to spontaneous ␥-H2AX focus formation as well as to elevated levels of sister chromatid exchanges.…”

Section: Discussionmentioning

confidence: 99%

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Human RECQ1 and RECQ4 Helicases Play Distinct Roles in DNA Replication Initiation

Thangavel

Mendoza-Maldonado

Tissino

et al. 2010

Molecular and Cellular Biology

132

139

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Cellular and biochemical studies support a role for all five human RecQ helicases in DNA replication; however, their specific functions during this process are unclear. Here we investigate the in vivo association of the five human RecQ helicases with three well-characterized human replication origins. We show that only RECQ1 (also called RECQL or RECQL1) and RECQ4 (also called RECQL4) associate with replication origins in a cell cycle-regulated fashion in unperturbed cells. RECQ4 is recruited to origins at late G 1 , after ORC and MCM complex assembly, while RECQ1 and additional RECQ4 are loaded at origins at the onset of S phase, when licensed origins begin firing. Both proteins are lost from origins after DNA replication initiation, indicating either disassembly or tracking with the newly formed replisome. Nascent-origin DNA synthesis and the frequency of origin firing are reduced after RECQ1 depletion and, to a greater extent, after RECQ4 depletion. Depletion of RECQ1, though not that of RECQ4, also suppresses replication fork rates in otherwise unperturbed cells. These results indicate that RECQ1 and RECQ4 are integral components of the human replication complex and play distinct roles in DNA replication initiation and replication fork progression in vivo.The RecQ helicases are a family of DNA-unwinding enzymes essential for the maintenance of genome integrity in all kingdoms of life. Five RecQ enzymes have been found in human cells: RECQ1 (also called RECQL or RECQL1), BLM (RECQ2 or RECQL3), WRN (RECQ3 or RECQL2), RECQ4 (RECQL4), and RECQ5 (RECQL5) (3, 7). Here we refer to these helicases as RECQ1, RECQ4, and RECQ5, without the "L" that is present in the official gene names. Mutations in the BLM, WRN, and RECQ4 genes are linked to Bloom syndrome (BS), Werner syndrome (WS), and the subset of RothmundThomson syndrome (RTS) patients at high risk of developing osteosarcomas, respectively (19,31,71). RECQ4 mutations have also been associated with RAPADILINO and BallerGerold syndrome (56, 61). Although these disorders are all associated with inherent genomic instability and cancer predisposition, they show distinct clinical features, suggesting that BLM, WRN, and RECQ4 are involved in different aspects of DNA metabolism. However, the molecular events underlying the pathogenesis of BS, WS, and RTS remain obscure. Mutations in the remaining two human RecQ helicase genes, RECQ1 and RECQ5, have not as yet been identified as causes of either genomic instability or heritable cancer predisposition disorders.Several lines of evidence suggest that RecQ helicases play an important role in DNA replication control (3, 10). In particular, RecQ helicases are thought to facilitate replication by preserving the integrity of stalled replication forks and by remodeling or repairing damaged or collapsed forks to allow the resumption of replication. Consistent with these ideas, several investigators have shown that primary fibroblasts from BS, WS, and RTS patients and RecQ5-deficient mouse embryonic fibroblasts all show differential...

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mentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Human RECQ1 and RECQ4 Helicases Play Distinct Roles in DNA Replication Initiation

Thangavel

Mendoza-Maldonado

Tissino

et al. 2010

Molecular and Cellular Biology

132

139

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“…The SsTop3 biochemical activities and the phenotype of the S. islandicus knock-out mutant suggest that it might play a role in genome stability. This mutant showed chromosome instability and defects in the coordination between replication and segregation (35), phenotypes recalling the aneuploidy typical of eukaryotic RecQ homolog mutants (48,49).…”

Section: Discussionmentioning

confidence: 99%

Synergic and Opposing Activities of Thermophilic RecQ-like Helicase and Topoisomerase 3 Proteins in Holliday Junction Processing and Replication Fork Stabilization

Valenti

Felice

Perugino

et al. 2012

Journal of Biological Chemistry

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Background: RecQ helicases and topoisomerase 3 enzymes play essential functions in all DNA activities, and their malfunctioning is associated with genomic instability. Results: A RecQ-like helicase and topoisomerase 3 from thermophilic archaea interact physically and functionally. Conclusion:The thermophilic enzymes show synergic and antagonistic activities on different DNA substrates. Significance: The results suggest a novel mechanism of modulation of RecQ-like helicases by topoisomerase 3 enzymes.

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“…3). These enzymes are involved in many of the processes of DNA metabolism, including recombination, DNA replication, and DNA repair (3)(4)(5). In humans, defects in RecQ family helicases, encoded by the blm, wrn, and RecQ4 genes, give rise to the Bloom, Werner, and Rothmund-Thomson syndromes, respectively, characterized by genomic instability and susceptibility to cancer.…”

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confidence: 99%

Multiple Escherichia coli RecQ Helicase Monomers Cooperate to Unwind Long DNA Substrates

Henry²,

Guiot³

et al. 2010

Journal of Biological Chemistry

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The RecQ family helicases catalyze the DNA unwinding reaction in an ATP hydrolysis-dependent manner. We investigated the mechanism of DNA unwinding by the Escherichia coli RecQ helicase using a new sensitive helicase assay based on fluorescence cross-correlation spectroscopy (FCCS) with two-photon excitation. The FCCS-based assay can be used to measure the unwinding activity under both single and multiple turnover conditions with no limitation related to the size of the DNA strands constituting the DNA substrate. We found that the monomeric helicase was sufficient to perform the unwinding of short DNA substrates. However, a significant increase in the activity was observed using longer DNA substrates, under single turnover conditions, originating from the simultaneous binding of multiple helicase monomers to the same DNA molecule. This functional cooperativity was strongly dependent on several factors, including DNA substrate length, the number and size of single-stranded 3-tails, and the temperature. Regarding the latter parameter, a strong cooperativity was observed at 37°C, whereas only modest or no cooperativity was observed at 25°C regardless of the nature of the DNA substrate. Consistently, the functional cooperativity was found to be tightly associated with a cooperative DNA binding mode. We also showed that the cooperative binding of helicase to the DNA substrate indirectly accounts for the sigmoidal dependence of unwinding activity on ATP concentration, which also occurs only at 37°C but not at 25°C. Finally, we further examined the influences of spontaneous DNA rehybridization (after helicase translocation) and the single-stranded DNA binding property of helicase on the unwinding activity as detected in the FCCS assay.Helicases are molecular motor enzymes that unwind and translocate nucleic acids in an ATP hydrolysis-dependent manner (1, 2). RecQ DNA helicases constitute a ubiquitous family of helicases that play a key role in maintaining genome stability in a wide range of organisms from bacteria to higher eukaryotes (for a review, see Ref.3). These enzymes are involved in many of the processes of DNA metabolism, including recombination, DNA replication, and DNA repair (3-5). In humans, defects in RecQ family helicases, encoded by the blm, wrn, and RecQ4 genes, give rise to the Bloom, Werner, and Rothmund-Thomson syndromes, respectively, characterized by genomic instability and susceptibility to cancer. The Escherichia coli RecQ helicase, the prototype enzyme of this family, is involved in various processes, including the homologous recombination and double strand break repair mediated by the RecF machinery (6) as well as suppression of illegitimate recombination (7).The structure-function relationship of helicases is difficult to understand at the molecular level, because proteins with different organizations may have similar activities. For example, the need for an oligomeric structure for helicase activity strongly varies between helicase families. Hexameric rings are required for active E. coli Dn...

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Unique and important consequences of RECQ1 deficiency in mammalian cells

Cited by 41 publications

References 118 publications

Human RECQ1 and RECQ4 Helicases Play Distinct Roles in DNA Replication Initiation

Human RECQ1 and RECQ4 Helicases Play Distinct Roles in DNA Replication Initiation

Synergic and Opposing Activities of Thermophilic RecQ-like Helicase and Topoisomerase 3 Proteins in Holliday Junction Processing and Replication Fork Stabilization

Multiple Escherichia coli RecQ Helicase Monomers Cooperate to Unwind Long DNA Substrates

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