Werner and Bloom helicases are involved in DNA repair in a complementary fashion

Imamura, Osamu; Fujita, Kumiko; Itoh, Chie; Takeda, Shunichi; Furuichi, Yasuhiro; Matsumoto, Takehisa

doi:10.1038/sj.onc.1205143

Cited by 95 publications

(78 citation statements)

References 70 publications

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“…Although our experiments were not designed to compare directly the effects of BLM and WRN on HR repair, the differences in HR repair frequencies were higher in BLM-/-cells than in WRN-/-cells. These results are in agreement with the finding that BLM is the dominant factor that regulates HR in avian cell lines (Imamura et al, 2002).…”

Section: Discussionsupporting

confidence: 83%

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WRN, the protein deficient in Werner syndrome, plays a critical structural role in optimizing DNA repair

et al. 2003

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SummaryWerner syndrome (WS) predisposes patients to cancer and premature aging, owing to mutations in WRN . The WRN protein is a RECQ-like helicase and is thought to participate in DNA double-strand break (DSB) repair by non-homologous end joining (NHEJ) or homologous recombination (HR). It has been previously shown that non-homologous DNA ends develop extensive deletions during repair in WS cells, and that this WS phenotype was complemented by wild-type ( Moreover, WRN appears to play a structural role, independent of its enzymatic activities, in optimizing HR and efficient NHEJ repair. Another human RECQ helicase, BLM, suppressed HR but had little or no effect on NHEJ, suggesting that mammalian RECQ helicases have distinct functions that can finely regulate recombination events.

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Section: Discussionsupporting

confidence: 83%

“…In this study, we investigated how the exonuclease and helicase activities of WRN, as opposed to its physical presence, regulate NHEJ and HR repair. In addition, we investigated the role of BLM, which was shown to play a more dominant role than WRN in HR (Imamura et al ., 2002), in these repair processes.…”

Section: Introductionmentioning

confidence: 99%

WRN, the protein deficient in Werner syndrome, plays a critical structural role in optimizing DNA repair

et al. 2003

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“…A recent study reported that both WRN and BLM may be involved in DNA repair in a complementary fashion. Based on measurements of hypersensitivity to DNA-damaging agents, synergism was observed when cells were deficient in both WRN and BLM proteins (45).…”

Section: Discussionmentioning

confidence: 99%

Colocalization, Physical, and Functional Interaction between Werner and Bloom Syndrome Proteins

Kobbe¹,

Karmakar²,

Dawut³

et al. 2002

Journal of Biological Chemistry

124

104

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The RecQ helicase family comprises a conserved group of proteins implicated in several aspects of DNA metabolism. Three of the family members are defective in heritable diseases characterized by abnormal growth, premature aging, and predisposition to malignancies. These include the WRN and BLM gene products that are defective in Werner and Bloom syndromes, disorders which share many phenotypic and cellular characteristics including spontaneous genomic instability. Here, we report a physical and functional interaction between BLM and WRN. These proteins were coimmunoprecipitated from a nuclear matrix-solubilized fraction, and the purified recombinant proteins were shown to interact directly. Moreover, BLM and WRN colocalized to nuclear foci in three human cell lines. Two regions of WRN that mediate interaction with BLM were identified, and one of these was localized to the exonuclease domain of WRN. Functionally, BLM inhibited the exonuclease activity of WRN. This is the first demonstration of a physical and functional interaction between RecQ helicases. Our observation that RecQ family members interact provides new insights into the complex phenotypic manifestations resulting from the loss of these proteins. Werner syndrome (WS)1 is a hallmark premature aging syndrome associated with increased malignancies and genomic instability (1). The protein defective in WS, Werner syndrome protein (WRN), is an ATP-dependent 3Ј-5Ј-helicase and also has a 3Ј-5Ј-exonuclease activity (2). Recently, a number of protein partners for WRN have been identified. These include proliferating cell nuclear antigen (3), replication protein A (RPA) (4), DNA topoisomerase I (3), the Ku heterodimer (5, 6), DNA polymerase ␦ (7), and p53 (8). Some of these interactions are not only physical but are also functional. Each of these binding proteins is involved in some form of DNA metabolism, such as DNA recombination, replication, and repair, and in the resolution of alternative DNA structures (1, 2). This suggests that WRN plays a role in a number of key DNA metabolic pathways. Bloom syndrome (BS) is a highly cancer-prone disease associated with increased genomic instability and elevated sister chromatid exchanges. The protein defective in this disorder, Bloom syndrome protein (BLM), is a 3Ј-5Ј-helicase (9). BLM binds to RPA, p53, topoisomerase III␣, and RAD51 and is a component of the BRCA1-associated genome surveillance complex (10). This links BLM with proteins implicated in several aspects of DNA metabolism (DNA recombination, replication, and repair).BLM and WRN both belong to the RecQ family of helicases, which are conserved from Escherichia coli to human (11). WRN is unique among the human RecQ helicases in having an exonuclease domain in the N-terminal region of the protein. A number of the RecQ helicases have been purified, and their biochemical properties have been characterized (11). There is considerable interest in the substrate specificities of each of these enzymes and in possible differences between them. However, so far there h...

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“…TRF2 also interacts with the DNA damage sensing protein ATM, and is thought to inhibit ATM activity specifically at telomeres [81], and WRN [82], the protein that is defective in the human premature aging and cancer-prone disorder Werner syndrome [83,84]. WRN encodes a DNA helicase and exonuclease [85,86] that appears to participate in both the NHEJ and HR DNA repair pathways [87][88][89][90][91][92][93][94]. It is not known whether all TRF1 complexes contain TANK1/2 and/or Ku, or whether all TRF2 complexes contain ATM, WRN, the RMN complex and/or other DNA damage sensors or repair proteins (Fig.…”

Section: Telomere-associated Proteins With Non-telomeric Functionsmentioning

confidence: 99%

Cancer and aging: the importance of telomeres in genome maintenance

Rodier

Kim

Nijjar

et al. 2005

The International Journal of Biochemistry & Cell Biology

120

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Telomeres are the specialized DNA-protein structures that cap the ends of linear chromosomes, thereby protecting them from degradation and fusion by cellular DNA repair processes. In vertebrate cells, telomeres consist of several kilobase pairs of DNA having the sequence TTAGGG, a few hundred base pairs of single-stranded DNA at the 3' end of the telomeric DNA tract, and a host of proteins that organize the telomeric double and single stranded DNA into a protective structure.

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Werner and Bloom helicases are involved in DNA repair in a complementary fashion

Cited by 95 publications

References 70 publications

WRN, the protein deficient in Werner syndrome, plays a critical structural role in optimizing DNA repair

WRN, the protein deficient in Werner syndrome, plays a critical structural role in optimizing DNA repair

Colocalization, Physical, and Functional Interaction between Werner and Bloom Syndrome Proteins

Cancer and aging: the importance of telomeres in genome maintenance

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