Replication Protein A Stimulates the Werner Syndrome Protein Branch Migration Activity

Sowd, Gregory A.; Wang, Hong; Pretto, Dalyir; Chazin, Walter J.; Opresko, Patricia L.

doi:10.1074/jbc.m109.049031

Cited by 25 publications

(20 citation statements)

References 71 publications

(120 reference statements)

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“…Interestingly, protein interaction studies have mapped RPA interaction domains within BLM 1–447 and WRN 239–499 [44]. Further, it is known that RPA interacts positively with BLM and WRN as they unwind DNA or branch migrate HJs [41, 72]. How then might the SE domain cooperate with the RecQ helicase?…”

Section: Discussionmentioning

confidence: 99%

Multimerization domains are associated with apparent strand exchange activity in BLM and WRN DNA helicases

Chen

Brill

2014

DNA Repair

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BLM and WRN are members of the RecQ family of DNA helicases that act to suppress genome instability and cancer predisposition. In addition to a RecQ helicase domain, each of these proteins contains an N-terminal domain of approximately 500 amino acids (aa) that is incompletely characterized. Previously, we showed that the N-terminus of Sgs1, the yeast ortholog of BLM, contains a physiologically important 200 aa domain (Sgs1103–322) that displays single-stranded DNA (ssDNA) binding, strand annealing (SA), and apparent strand-exchange (SE) activities in vitro. Here we used a genetic assay to search for heterologous proteins that could functionally replace this domain of Sgs1 in vivo. In contrast to Rad59, the oligomeric Rad52 protein provided in vivo complementation, suggesting that multimerization is functionally important. An N-terminal domain of WRN was also identified that could replace Sgs1103–322 in yeast. This domain, WRN235–526, contains a known coiled coil and displays the same SA and SE activities as Sgs1103–322. The coiled coil domain of WRN235–526 was found to be required for both its in vivo activity and its in vitro SE activity. Based on this result, a potential coiled coil was identified within Sgs1103–322. This 25 amino acid region was similarly essential for wt Sgs1 activity in vivo and was replaceable by a heterologous coiled coil. Taken together, the results indicate that a coiled coil and a closely-linked apparent SE activity are conserved features of the BLM and WRN DNA helicases.

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Section: Discussionmentioning

confidence: 99%

Multimerization domains are associated with apparent strand exchange activity in BLM and WRN DNA helicases

Chen

Brill

2014

DNA Repair

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“…RPA interaction with RecQ helicase family member BLM or WRN can inhibit replication fork stalling caused by noncanonical DNA structures (50)(51)(52)(53). The fact that TNRs form hairpin structures in human cells (8) suggests that intrastrand hairpin forma- 45 TNR instability during unperturbed cell culture.…”

Section: Discussionmentioning

confidence: 99%

Oligodeoxynucleotide Binding to (CTG) · (CAG) Microsatellite Repeats Inhibits Replication Fork Stalling, Hairpin Formation, and Genome Instability

Liu

Chen

Leffak

2013

Molecular and Cellular Biology

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(CTG) n · (CAG) n trinucleotide repeat (TNR) expansion in the 3= untranslated region of the dystrophia myotonica protein kinase (DMPK) gene causes myotonic dystrophy type 1. However, a direct link between TNR instability, the formation of noncanonical (CTG) n · (CAG) n structures, and replication stress has not been demonstrated. In a human cell model, we found that (CTG) 45 · (CAG) 45 causes local replication fork stalling, DNA hairpin formation, and TNR instability. Oligodeoxynucleotides (ODNs) complementary to the (CTG) 45 · (CAG) 45 lagging-strand template eliminated DNA hairpin formation on leading-and laggingstrand templates and relieved fork stalling. Prolonged cell culture, emetine inhibition of lagging-strand synthesis, or slowing of DNA synthesis by low-dose aphidicolin induced (CTG) 45 · (CAG) 45 expansions and contractions. ODNs targeting the laggingstrand template blocked the time-dependent or emetine-induced instability but did not eliminate aphidicolin-induced instability. These results show directly that TNR replication stalling, replication stress, hairpin formation, and instability are mechanistically linked in vivo.

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“…After which, it can reverse, bypassing the lesion or prohibitive structure, and replication can proceed (28). It has been proposed that the exonuclease domain on WRN, not found in any other RecQ helicase, may assist in this processing (45). An important aspect of this model is that replication of the strands can be uncoupled-that is, one strand's replication can proceed if the other is stalled-allowing both strand invasion and reverse chicken-foot structure formation to occur.…”

Section: Discussionmentioning

confidence: 99%

Hyper telomere recombination accelerates replicative senescence and may promote premature aging

Hagelstrom

Blagoev

Niedernhofer

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Werner syndrome and Bloom syndrome result from defects in the RecQ helicases Werner (WRN) and Bloom (BLM), respectively, and display premature aging phenotypes. Similarly, XFE progeroid syndrome results from defects in the ERCC1-XPF DNA repair endonuclease. To gain insight into the origin of cellular senescence and human aging, we analyzed the dependence of sister chromatid exchange (SCE) frequencies on location [i.e., genomic (G-SCE) vs. telomeric (T-SCE) DNA] in primary human fibroblasts deficient in WRN, BLM, or ERCC1-XPF. Consistent with our other studies, we found evidence of elevated T-SCE in telomerase-negative but not telomerase-positive backgrounds. In telomerase-negative WRN-deficient cells, T-SCE—but not G-SCE—frequencies were significantly increased compared with controls. In contrast, SCE frequencies were significantly elevated in BLM-deficient cells irrespective of genome location. In ERCC1-XPF-deficient cells, neither T- nor G-SCE frequencies differed from controls. A theoretical model was developed that allowed an in silico investigation into the cellular consequences of increased T-SCE frequency. The model predicts that in cells with increased T-SCE, the onset of replicative senescence is dramatically accelerated even though the average rate of telomere loss has not changed. Premature cellular senescence may act as a powerful tumor-suppressor mechanism in telomerase-deficient cells with mutations that cause T-SCE levels to rise. Furthermore, T-SCE-driven premature cellular senescence may be a factor contributing to accelerated aging in Werner and Bloom syndromes, but not XFE progeroid syndrome.

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Replication Protein A Stimulates the Werner Syndrome Protein Branch Migration Activity

Cited by 25 publications

References 71 publications

Multimerization domains are associated with apparent strand exchange activity in BLM and WRN DNA helicases

Multimerization domains are associated with apparent strand exchange activity in BLM and WRN DNA helicases

Oligodeoxynucleotide Binding to (CTG) · (CAG) Microsatellite Repeats Inhibits Replication Fork Stalling, Hairpin Formation, and Genome Instability

Hyper telomere recombination accelerates replicative senescence and may promote premature aging

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