RecQ helicase, in concert with RecA and SSB proteins, initiates and disrupts DNA recombination

Harmon, Frank G.; Kowalczykowski, Stephen C.

doi:10.1101/gad.12.8.1134

Cited by 259 publications

(236 citation statements)

References 58 publications

Supporting

Mentioning

224

Contrasting

Order By: Relevance

“…These biochemical observations support a role for BLM in preventing chromosome crossing-over by disrupting joint molecules before they mature into Holliday junctions. Our results and model do not deny the participation of BLM in these additional late functions; rather, the pleiotropic role of BLM in recombination is comparable with that of E. coli RecQ, which can act both early to initiate recombination and late to disrupt joint molecules and decatenate junctions (23,24).…”

Section: Discussionmentioning

confidence: 78%

“…BLM is a member of this RecQ family (16) and has been implicated in branch migration (17), disruption of joint molecules (18)(19)(20), and processing of double Holliday junctions by interaction with Rmi1 and topoisomerase III␣ (19,21,22), all late functions. However, E. coli RecQ functions both early and late in recombination (1,11,23) by stimulating RecJ (N. Handa, K. Morimatsu, S. T. Lovett, and S.C.K., unpublished observations) and cooperating with topoisomerase III (24), respectively. Thus, we examined whether BLM might also have multiple functions and could stimulate hExo1 to mimic RecQ and RecJ behavior functionally.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Human exonuclease 1 and BLM helicase interact to resect DNA and initiate DNA repair

Nimonkar

Özsoy

Genschel³

et al. 2008

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

269

236

View full text Add to dashboard Cite

The error-free repair of double-stranded DNA breaks by homologous recombination requires processing of broken ends. These processed ends are substrates for assembly of DNA strand exchange proteins that mediate DNA strand invasion. Here, we establish that human BLM helicase, a member of the RecQ family, stimulates the nucleolytic activity of human exonuclease 1 (hExo1), a 5 33 double-stranded DNA exonuclease. The stimulation is specific because other RecQ homologs fail to stimulate hExo1. Stimulation of DNA resection by hExo1 is independent of BLM helicase activity and is, instead, mediated by an interaction between the 2 proteins. Finally, we show that DNA ends resected by hExo1 and BLM are used by human Rad51, but not its yeast or bacterial counterparts, to promote homologous DNA pairing. This in vitro system recapitulates initial steps of homologous recombination and provides biochemical evidence for a role of BLM and Exo1 in the initiation of recombinational DNA repair.Bloom syndrome ͉ Rad51 ͉ recombination ͉ RecQ ͉ DNA pairing H omologous recombination contributes toward the maintenance of genomic integrity by accurately repairing doublestranded DNA (dsDNA) breaks. The recombinational repair of dsDNA breaks (DSBs) proceeds by successive reactions that start with processing of the broken DNA ends to reveal single-stranded DNA (ssDNA) (1). Processing requires the action of a helicase and/or nuclease. The resultant 3Ј-terminated ssDNA is used by a DNA strand exchange protein as the substrate for assembly of the nucleoprotein filament that is the active species in the search for homologous DNA and subsequent DNA pairing. It is unclear which enzymes in eukaryotes resect the DNA break to initiate recombination; however, much is known about the process in bacteria. In Escherichia coli, recombinational DNA repair occurs by either the RecBCD or the RecF pathway (1). RecBCD is a helicase/nuclease that processes dsDNA to produce 3Ј-tailed ssDNA onto which RecA is loaded. In the RecF pathway, a separate helicase and nuclease are used for resection of DSBs and ssDNA-gaps: RecQ, a 3Ј35Ј helicase, and RecJ, a 5Ј33Ј exonuclease (1).

show abstract

Section: Discussionmentioning

confidence: 78%

mentioning

confidence: 99%

Human exonuclease 1 and BLM helicase interact to resect DNA and initiate DNA repair

Nimonkar

Özsoy

Genschel³

et al. 2008

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

269

236

View full text Add to dashboard Cite

show abstract

“…A lot of evidence, regarding mainly studies on bacterial and yeast model systems, suggests that RecQ family of helicases may resolve aberrant DNA structures that arise from DNA metabolic processes such as replication, recombination, and repair (Harmon and Kowalczykowski, 1998;Chakraverty and Hickson, 1999;Karow et al, 2000). In particular, bacterial and yeast RecQ helicases seem to be involved in the suppression of illegitimate recombination after collapse and disassembly of the replication fork, caused either by replication arrest or DNA damage (reviewed by Kuzminov, 1995;Chakraverty and Hickson, 1999;Michel, 2000).…”

Section: Resultsmentioning

confidence: 99%

Werner's Syndrome Protein Is Required for Correct Recovery after Replication Arrest and DNA Damage Induced in S-Phase of Cell Cycle

Pichierri

Franchitto

Mosesso

et al. 2001

MBoC

137

140

View full text Add to dashboard Cite

Werner's syndrome (WS) is a rare autosomal recessive disorder that arises as a consequence of mutations in a gene coding for a protein that is a member of RecQ family of DNA helicases, WRN. The cellular function of WRN is still unclear, but on the basis of the cellular phenotypes of WS and of RecQ yeast mutants, its possible role in controlling recombination and/or in maintenance of genomic integrity during S-phase has been envisaged. With the use of two drugs, camptothecin and hydroxyurea, which produce replication-associated DNA damage and/or inhibit replication fork progression, we find that WS cells have a slower rate of repair associated with DNA damage induced in the S-phase and a reduced induction of RAD51 foci. As a consequence, WS cells undergo apoptotic cell death more than normal cells, even if they arrest and resume DNA synthesis at an apparently normal rate. Furthermore, we report that WS cells show a higher background level of DNA strand breaks and an elevated spontaneous induction of RAD51 foci. Our findings support the hypothesis that WRN could be involved in the correct resolution of recombinational intermediates that arise from replication arrest due to either DNA damage or replication fork collapse. INTRODUCTIONWerner's syndrome (WS) is a rare autosomal recessive disorder characterized by premature aging (Salk et al., 1985) and early onset of various neoplasms, including different types of carcinomas and sarcomas (Goto et al., 1981;Hrabko et al., 1982;Sato et al., 1988). This disorder arises as a consequence of mutations in a gene coding for a protein that is a member of RecQ family of DNA helicases, WRN. One of the hallmarks of WS patients is the genomic instability as evidenced by the spontaneous chromosome anomalies and large deletions in many genes (Salk et al., 1985;Fukuchi et al., 1989). It has been demonstrated that WRN exhibits DNA unwinding activity (Gray et al., 1997;Suzuki et al., 1997) and exonuclease activity residing in the N-terminal region (Huang et al., 1998). The cellular function of WRN is still unclear. It has been proposed that helicases are required for various DNA metabolic activities, including progression of replication fork, segregation of newly replicated chromosomes, disruption of the nucleosome structure, DNA supercoiling, transcription, recombination, and repair (Duguet, 1997). In addition, it has been suggested that RecQ family of DNA helicases has an important role in the maintenance of genomic integrity during DNA replication . Studies from yeast show that DNA replication does not proceed normally in absence of RecQ helicase function (Stewart et al., 1997) and in Xenopus laevis the ortholog of WRN is absolutely required for proper formation of replication foci (Yan et al., 1998). Functional interaction between proteins involved in DNA replication, such as replication protein A (RPA) and DNA polymerase ␦, and WRN also have been reported (Shen et al., 1998;Brosh et al., 1999;Kamath-Loeb et al., 2000). Furthermore, in yeast, the RecQlike proteins seem involved in ...

show abstract

“…RecQ is a component of the RecF pathway, which is required for recombinational repair, that is essential for nearly all nondouble-strand break recombination in E. coli (41,42,52). Because of its helicase activity that can unwind DNA at broken ends, the RecQ protein, together with the RecJ 5Ј-3Ј nuclease, was proposed to act as functional analogs of the RecBCD helicase/nuclease in the RecBCD pathway during recombination repair (21).…”

mentioning

confidence: 99%

Multiple Genetic Pathways Involving the Caenorhabditis elegans Bloom's Syndrome Genes him-6, rad-51, and top-3 Are Needed To Maintain Genome Stability in the Germ Line

Wicky

Alpi

Passannante

et al. 2004

Molecular and Cellular Biology

View full text Add to dashboard Cite

Bloom's syndrome (BS) is an autosomal-recessive human disorder caused by mutations in the BS RecQ helicase and is associated with loss of genomic integrity and an increased incidence of cancer. We analyzed the mitotic and the meiotic roles of Caenorhabditis elegans him-6, which we show to encode the ortholog of the human BS gene. Mutations in him-6 result in an enhanced irradiation sensitivity, a partially defective S-phase checkpoint, and in reduced levels of DNA-damage induced apoptosis. Furthermore, him-6 mutants exhibit a decreased frequency of meiotic recombination that is probably due to a defect in the progression of crossover recombination. In mitotically proliferating germ cells, our genetic interaction studies, as well as the assessment of the number of double-strand breaks via RAD-51 foci, reveal a complex regulatory network that is different from the situation in yeast. Although the number of double-strand breaks in him-6 and top-3 single mutants is elevated, the combined depletion of him-6 and top-3 leads to mitotic catastrophe concomitant with a massive increase in the level of double-strand breaks, a phenotype that is completely suppressed by rad-51. him-6 and top-3 are thus needed to maintain low levels of double-strand breaks in normally proliferating germ cells, and both act in partial redundant pathways downstream of rad-51 to prevent mitotic catastrophy. Finally, we show that topoisomerase III␣ acts independently during a late stage of meiotic recombination.

show abstract

RecQ helicase, in concert with RecA and SSB proteins, initiates and disrupts DNA recombination

Cited by 259 publications

References 58 publications

Human exonuclease 1 and BLM helicase interact to resect DNA and initiate DNA repair

Human exonuclease 1 and BLM helicase interact to resect DNA and initiate DNA repair

Werner's Syndrome Protein Is Required for Correct Recovery after Replication Arrest and DNA Damage Induced in S-Phase of Cell Cycle

Multiple Genetic Pathways Involving the Caenorhabditis elegans Bloom's Syndrome Genes him-6, rad-51, and top-3 Are Needed To Maintain Genome Stability in the Germ Line

Contact Info

Product

Resources

About