RecQ helicases: multiple roles in genome maintenance

Khakhar, Rakesh R; Cobb, Jennifer A.; Bjergbæk, Lotte; Hickson, Ian D.; Gasser, Susan M.

doi:10.1016/s0962-8924(03)00171-5

Cited by 113 publications

(115 citation statements)

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“…Other characterized mammalian helicases do not exhibit extensive redundancy in vivo. For example, the five known RecQ helicases (Wrn, Blm, RecQ4, RecQL, and RecQ5b) and XPB/ ERCC3 (implicated in xeroderma pigmentosum and Cockayne syndrome) show limited redundancy in rescuing p53-dependent apoptosis in Bloom-deficient cells (63); however, mutations in each helicase gene have distinct phenotypes in genome stability and DNA replication and repair in vivo and all are separately implicated in human disease (8,34,49,62).…”

Section: Discussionmentioning

confidence: 99%

“…The Ku70/Ku80 heterodimer, while essential for nonhomologous end joining, also plays a key role both in the recruitment of telomerase to the telomere and in the protection of ends from degradation (9,25,65,74). Several DNA helicases and nucleases are also known to play key roles in the replication and maintenance of telomeres, including Pif1, Sgs1, Mre11, Rtel, and others (20,34,41).Pif1 is a member of a 5Ј-to-3Ј DNA helicase family whose other closest members include Rrm3 and, in Schizosaccharomyces pombe, Pfh1 (33,37,77). Unlike Rrm3 and Pif1, Pfh1 is essential (77).…”

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confidence: 99%

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Murine Pif1 Interacts with Telomerase and Is Dispensable for Telomere Function In Vivo

Snow

Mateyak

Paderova

et al. 2007

Molecular and Cellular Biology

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Pif1 is a 5 -to-3 DNA helicase critical to DNA replication and telomere length maintenance in the budding yeast Saccharomyces cerevisiae. ScPif1 is a negative regulator of telomeric repeat synthesis by telomerase, and recombinant ScPif1 promotes the dissociation of the telomerase RNA template from telomeric DNA in vitro. In order to dissect the role of mPif1 in mammals, we cloned and disrupted the mPif1 gene. In wild-type animals, mPif1 expression was detected only in embryonic and hematopoietic lineages. mPif1 ؊/؊ mice were viable at expected frequencies, displayed no visible abnormalities, and showed no reproducible alteration in telomere length in two different null backgrounds, even after several generations. Spectral karyotyping of mPif1 ؊/؊ fibroblasts and splenocytes revealed no significant change in chromosomal rearrangements. Furthermore, induction of apoptosis or DNA damage revealed no differences in cell viability compared to what was found for wild-type fibroblasts and splenocytes. Despite a novel association of mPif1 with telomerase, mPif1 did not affect the elongation activity of telomerase in vitro. Thus, in contrast to what occurs with ScPif1, murine telomere homeostasis or genetic stability does not depend on mPif1, perhaps due to fundamental differences in the regulation of telomerase and/or telomere length between mice and yeast or due to genetic redundancy with other DNA helicases.Homeostatic telomere length is achieved by a balance between the extension of the 3Ј telomeric repeats by telomerase or by homologous recombination between telomeric tracts and telomere erosion due to incomplete DNA replication or nucleolytic degradation (30). Telomerase acts to lengthen telomeres via the reverse transcription of an RNA template (encoded by TERC in mammals or TLC1 in Saccharomyces cerevisiae) by a telomerase reverse transcriptase (TERT or Est2, respectively) (30). In the absence of telomerase, telomeric repeats can also be maintained via homologous recombination (12). Excessive telomere lengthening is usually curtailed by cis-inhibitory telomere binding factors, such as Rif1 and Rap1 in S. cerevisiae and TRF1 in humans, or by the action of nucleases (30). In particular instances, telomeric tracts undergo saltatory attrition via the excision of telomeric DNA circles, thus preventing unregulated telomere lengthening (12,40,73).This equilibrium is not simply a push and pull between factors that strictly promote or oppose telomere extension. In S. cerevisiae, the trimeric protein complex composed of Cdc13, Stn1, and Ten1 plays a critical role in the protection of chromosome ends from nucleolytic degradation, and the complex serves both positive and negative roles in the access of telomerase to the telomere during late S phase (24,27,66). The Ku70/Ku80 heterodimer, while essential for nonhomologous end joining, also plays a key role both in the recruitment of telomerase to the telomere and in the protection of ends from degradation (9,25,65,74). Several DNA helicases and nucleases are also known to play ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Murine Pif1 Interacts with Telomerase and Is Dispensable for Telomere Function In Vivo

Snow

Mateyak

Paderova

et al. 2007

Molecular and Cellular Biology

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“…In response to an upstream signal, transducers activate downstream partners, for example, by recruiting appropriate repair enzymes to specific sites of DNA damage. As mentioned, Sgs1 appears to function in the S-phase checkpoint pathway (6,30). BLM may act early in response to DNA damage during S-phase, because BLM was recently reported to be required for efficient localization of protein factors to repair complexes/foci after replication fork stalling (65)(66)(67).…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 98%

“…Evidence in yeast indicates that Sgs1 participates in the S-phase checkpoint response to DNA damage (6). In mammalian cells, WRN tyrosine phosphorylation is induced by bleomycin (␥-irradiation mimic) in a manner dependent on the c-Abl kinase DNA damage response pathway (61).…”

Section: Roles In Other Dna Repair Pathwaysmentioning

confidence: 99%

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Junction of RecQ Helicase Biochemistry and Human Disease

Opresko

Cheng

Bohr

2004

Journal of Biological Chemistry

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RecQ helicases are a family of conserved enzymes required for maintaining the genomic integrity, that function as suppressors of inappropriate recombination. Mutations in Escherichia coli RecQ and in the Saccharomyces cerevisiae RecQ homolog, Sgs1, result in an increased frequency of illegitimate recombination (1). In humans, defects in three RecQ family proteins are associated with rare autosomal-recessive disorders characterized by genomic instability and increased cancer susceptibility. Mutations in WRN, BLM, and RECQ4 give rise to the disorders Werner syndrome (WS), 1 Bloom syndrome (BS), and Rothmund-Thomson syndrome (RTS), respectively, the clinical features of which have been reviewed elsewhere (2). Briefly, BS patients are predisposed to many types of cancer with the mean age of onset of 24. WS patients are especially predisposed to sarcomas, premature aging, and ageassociated diseases. RTS patients have a characteristic rash, poikiloderma, and are predisposed to osteosarcomas and some features of premature aging. The molecular basis of genomic instability and premature aging is not well understood.The RecQ family is named after E. coli RecQ helicase, a well characterized prototypical member (Fig. 1). Helicases separate complementary strands of nucleic acids in a reaction coupled to NTP hydrolysis. RecQ helicases have a common helicase domain, which binds and hydrolyzes ATP. Most RecQ helicases have a highly conserved multifunctional RecQ C-terminal region (RQC) and a helicase RNase D C-terminal (HRDC) domain (Fig. 1). A recent report of the x-ray crystal structure for the E. coli RecQ catalytic core indicates that the RQC domain contains DNA and protein binding motifs (3). Consistent with this, the RQC domain of WRN binds to various DNA substrates and mediates interactions with other proteins involved in DNA metabolism (4). The E. coli RecQ HRDC domain is required for stable DNA binding but not for catalytic activity (5). Similarly, the HRDC domain of human WRN also binds DNA substrates but is not required for catalytic activity (4). Two RecQ family proteins WRN and Xenopus laevis FFA-1 also have an exonuclease domain. Bacteria and yeast have a single RecQ family member, and up to five RecQ members have been found in mammals.To better define the precise roles of RecQ helicases in vivo, significant research effort has been devoted to characterizing the biochemical properties of RecQ helicases and to identifying important protein interactions between RecQ helicases and other well characterized proteins. This review will focus primarily on these aspects and on the most well characterized RecQ helicases, due to space limitations. RecQ helicase genetic studies in yeast have been recently reviewed elsewhere (6). Biochemical Characteristics of RecQ HelicasesAll RecQ helicases purified and characterized to date unwind duplex DNA in a 3Ј to 5Ј direction with respect to the DNA strand bound by the helicase. Substrate preferences are determined by comparing product amounts, reaction kinetics, and/or protein affini...

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Genomic Instability andDNARepair

Gagos

2007

The Cancer Handbook

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There is growing evidence that genomic instability is both an epiphenomenon and a leading cause of cancer. Chromosomal instability in neoplasia (CIN) is the most frequent type of genomic instability in solid tumours. For more than a century, chromosomal rearrangements and aneuploidy in neoplasia have been extensively studied and a vast number of genes and pathways, directly or indirectly implicated in CIN, have been described. Chromosomal abnormalities in cancer generate huge genomic imbalances and tumour heterogeneity. This chapter addresses the role of genes, chromosome structure, and telomere dysfunction in the initiation and perpetuation of CIN. The biological consequences of large chromosomal imbalances are discussed and the long‐standing hypotheses for the generation of chromosomal anomalies in neoplasia are re‐examined under the context of telomere dysfunction and restoration.

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RecQ helicases: multiple roles in genome maintenance

Cited by 113 publications

References 67 publications

Murine Pif1 Interacts with Telomerase and Is Dispensable for Telomere Function In Vivo

Murine Pif1 Interacts with Telomerase and Is Dispensable for Telomere Function In Vivo

Junction of RecQ Helicase Biochemistry and Human Disease

Genomic Instability andDNARepair

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