Resolving RAD51C function in late stages of homologous recombination
© Sharan and Kuznetsov; licensee BioMed Central Ltd. 2007
Received: 16 May 2007
Accepted: 04 June 2007
Published: 04 June 2007
DNA double strand breaks are efficiently repaired by homologous recombination. One of the last steps of this process is resolution of Holliday junctions that are formed at the sites of genetic exchange between homologous DNA. Although various resolvases with Holliday junctions processing activity have been identified in bacteriophages, bacteria and archaebacteria, eukaryotic resolvases have been elusive. Recent biochemical evidence has revealed that RAD51C and XRCC3, members of the RAD51-like protein family, are involved in Holliday junction resolution in mammalian cells. However, purified recombinant RAD51C and XRCC3 proteins have not shown any Holliday junction resolution activity. In addition, these proteins did not reveal the presence of a nuclease domain, which raises doubts about their ability to function as a resolvase. Furthermore, oocytes from infertile Rad51C mutant mice exhibit precocious separation of sister chromatids at metaphase II, a phenotype that reflects a defect in sister chromatid cohesion, not a lack of Holliday junction resolution. Here we discuss a model to explain how a Holliday junction resolution defect can lead to sister chromatid separation in mouse oocytes. We also describe other recent in vitro and in vivo evidence supporting a late role for RAD51C in homologous recombination in mammalian cells, which is likely to be resolution of the Holliday junction.
Although many resolvases have been identified in prokaryotes, few have been found in eukaryotes. The yeast CCE1 is encoded by a nuclear gene but functions as a resolvase in the mitochondria [9, 17]. Identification of the Mus81-Eme1 endonuclease in Saccharomyces pombe raised hopes that the eukaryotic resolvase has been identified . It has a substrate preference for nicked HJs and displacement loops (D-loops) . Genetic studies showed that S. pombe mus81 mutants are infertile due to failed meiotic recombination, which could be rescued by the expression of bacterial RusA resolvase . These studies demonstrated that Mus81 is indeed a eukaryotic resolvase. The homologs of fission yeast Mus81-Eme1 have been identified in other organisms, including Saccharomyces cereviciae (Mus81-Mms4), Arabidopsis (AtMUS81/At4g30870) and humans (Mus81-Eme1 or Mms4) [20–26]. However, unlike the S. pombe mutants, S. cereviciae mus81 mutants are partially fertile, and MUS81-deficient Arabidopsis plants and mice are fully fertile, with no defect in meiotic recombination [21–23, 27, 28]. These observations suggest the presence of other resolvases in these organisms. Also, it was shown that the HJ resolution activity in mammalian cells could be separated from MUS81, suggesting that MUS81 was not the mammalian HJ resolvase .
The idea that RAD51 paralogs may be involved in resolution of HJs came from the observation that the protein fraction with HJ resolution activity contained RAD51C and XRCC3, members of the RAD51-like protein family . This observation was very exciting considering that members of this family were already known to play a role during the early stages of homologous recombination. In higher eukaryotes, including plants, chicken and mammals, there are six members of the RAD51-like protein family that show 20–30% sequence similarity to RAD51 [31, 32]. These are RAD51B/RAD51L1, RAD51C/RAD51L2, RAD51D/RAD51L3, XRCC2, XRCC3 and DMC1. DMC1 shares about 50% sequence identity with RAD51and is its structural and functional homolog that functions specifically in meiotic recombination . The other five paralogs show 20–30% sequence similarity to RAD51 and have been shown to be part of at least two distinct protein complexes, namely, the BCDX2 and CX3 complexes . The BCDX2 complex comprises RAD51B, RAD51C, RAD51D and XRCC2 proteins; the CX3 complex consists of RAD51C and XRCC3. All these RAD51 paralogs have been reported to be required for normal proliferation and play a role in RAD51-mediated homologous recombination .
Studies in chicken B-lymphocyte DT40 cells have shown that only RAD51 is essential for cell viability, while loss of other RAD51 paralogs does not affect cell survival . Interestingly, although mutants lacking any of the RAD51 paralogs show sensitivity to DNA-damaging agents, their phenotypes are not identical, suggesting that their function is similar but not redundant . This functional non-redundancy is corroborated by the loss-of-function studies in mice and Arabidopsis [37–40]. Depletion of RAD51C by siRNA in human cells also suggests that RAD51C plays a role in homologous recombinational repair . These findings are consistent with the idea that these paralogs play a role in early stages of homologous recombination. Recent work from Stephen West's laboratory has suggested that RAD51C and XRCC3 may also play a role in the late stages of homologous recombination [30, 42]. Here we discuss various findings that support the dual role of RAD51C.
The role of RAD51C and XRCC3 in HJ resolution
In a very significant study, Liu et al. demonstrated that RAD51C is required for the resolution of HJs in mammalian cells . After an intricate series of HeLa cell nuclear extract fractionations, fractions with HJ resolution and branch migration activity were identified. These fractions lacked some of the possible candidates like Mus81, Flap endonuclease 1 (FEN1), RecQ DNA helicase (BLM) and Werner syndrome helicase (WRN). On the other hand, all the fractions with HJ resolution activity contained RAD51C. Immunodepletion using a RAD51C antibody resulted in the loss of the HJ processing function. This activity could be restored by adding purified RAD51 paralog protein complexes containing RAD51C, but not those lacking it. These studies directly implicated RAD51C in the resolution process. Furthermore, the Chinese hamster ovary cell line irs3 defective in RAD51C was shown to lack the HJ processing function. Recently, mouse embryonic fibroblasts generated from Rad51c knockout embryos revealed marked reduction in HJ activity . Interestingly, a hamster cell line with mutant XRCC3, irs1SF, also showed a defect in HJ resolution activity, while mutation in another RAD51 paralog, XRCC2, had no effect on HJ resolution . Although Liu et al. provided strong evidence to show the involvement of both RAD51C as well as XRCC3 in the resolution of HJ, a direct cleavage of the HJ structure by purified recombinant proteins remains to be demonstrated. It is possible that these proteins undergo posttranslational modifications, which may be essential for the HJ processing function. This theory is supported by the observation that the mobility of the RAD51C present in the fractions of HeLa cell extract that possess HJ resolution function is different from the mobility of those present in unfractionated whole cell extracts. Identifying the nature of this modification may elucidate the structural or conformational change in RAD51C that may be essential to its HJ resolution activity.
More recently, in a follow-up study, Liu et al. provide new biochemical evidence to link RAD51C and XRCC3 to the HJ processing function . Using affinity chromatography, they showed a direct link between RAD51C and HJ activity. In a nickel column loaded with recombinant His-tagged RAD51C protein, HJ activity present in HeLa cell extracts was shown to bind to the column, which could subsequently be eluted. XRCC3 present in the extract was also shown to bind to the column and elute with HJ activity. Using gel filtration, the HJ resolvase activity was found to elute with an average molecular mass of 80–90 kDa, similar to the sum of the molecular masses of RAD51C (~42 kDa) and XRCC3 (~38 kDa). This finding suggests that the RAD51C-XRCC3 heterodimer should have the HJ activity. Because efforts to demonstrate this activity using purified recombinant proteins have failed, it has been speculated that the resolvosome complex may contain an additional component, such as a small nuclease, which may be essential for the HJ resolution function of the RAD51C-XRCC3 dimer. This suggestion may also explain the absence of any apparent nuclease domain in RAD51C or XRCC3. Future studies aimed at determining whether the HJ resolvosome complex involves other component(s) in addition to RAD51C and XRCC3 are important.
Localization of RAD51C on meiotic chromosomes
In addition to the biochemical studies, Liu et al. have presented interesting immunofluorescence data showing the localization of RAD51C on meiotic chromosomes, which further supports its role in late stages of homologous recombination . Since various stages of meiotic prophase I coincide well with different stages of double-strand-break (DSB) repair by homologous recombination, it is possible to associate the function of a protein based on its localization on meiotic chromosomes at any given prophase I stage. Interestingly, RAD51C was first detected at the pachytene stage, when it was observed as one or two distinct foci associated with each synapsed bivalent. This pattern of expression is similar to the foci formed by the mismatch repair protein MLH1 . These foci are believed to represent the sites of crossovers, formed as a result of recombination between homologous chromosomes. In addition, spermatocytes from Mlh1-deficient mice, which have a severely reduced number of crossover sites, also showed a marked reduction in RAD51C foci. This observation strengthens the notion that RAD51C foci formation during pachytene depends on the generation of crossovers, which is one of the last steps of homologous recombination. Surprisingly, co-localization of MLH1 and RAD51C foci on the bivalents was not observed. Also, XRCC3 foci were not detected on these bivalents. These observations raise concerns and are currently difficult to explain. The lack of co-localization of RAD51C and MLH1 may be due to temporal differences in their localization at crossover sites. It is interesting that, although no XRCC3 foci were observed on autosomal bivalents, XRCC3 foci, along with RAD51C and MLH1 foci, were present in the pseudoautosomal region of the sex chromosomes, a region on X and Y chromosomes that undergoes an obligatory crossover event. These foci in the pseudoautosomal region were not detected in Mlh1-deficient spermatocytes, supporting their dependence on a crossover event.
It was surprising that Liu et al. did not detect RAD51C foci during the leptotene and zygotene stages of prophase I, where it is expected to play an important role based on its known function in the early stages of homologous recombination. However, failure to observe RAD51C foci does not rule out its functional importance at this stage. Different antibodies and more sensitive imaging methods may help resolve this discrepancy. In the meantime, it may be interesting to examine the consequence of the loss of these proteins in an in vivo model system. In Drosophila, the loss of RAD51C-like protein encoded by spn-D gene results in a meiosis-specific defect and may play a role similar to DMC1 . Recent studies in Arabidopsis revealed that RAD51C is essential for repair of Spo11-induced DSBs during prophase I of meiosis [40, 46]. Homologous chromosomes in Rad51c-deficient plant meiocytes fail to synapse and become severely fragmented. These results support a role for RAD51C early in meiotic recombination but do not shed light on its role later in the process.
RAD51C function in meiosis
Because RAD51C is predicted to have a dual function, an early and a late role in homologous recombination, it may be difficult to demonstrate the latter function in vivo, as a defect in the former may result in the arrest of meiocytes. Because RAD51C-deficient mice die during embryogenesis and no suitable meiosis-specific Cre transgenic mouse line is available yet, it is a challenge to generate a suitable mouse model to study the meiotic functions of RAD51C. We recently reported the generation of a hypomorphic allele of Rad51c that results in a reduction of the protein level due to aberrant splicing . This aberrant splicing is caused by the presence of the neomycin resistance gene in one of the introns. Mice that are homozygous for the hypomorphic allele and have about 60% reduction in RAD51C protein level are viable and fertile. However, mice with only one copy of the hypomorphic allele (while the other allele is a null) are viable, but 35% of males and 12% of females are infertile. The infertile males and females provide an ideal in vivo model system to study the role of RAD51C in meiotic recombination. In addition, the meiotic phenotype associated with the loss of RAD51C function is sexually dimorphic, showing an early meiotic defect in males and a late defect in females, which provides a unique opportunity to study the dual function of RAD51C in mouse meiosis.
Infertile males revealed an early role for RAD51C in meiosis, marked by the spermatocyte arrest at leptotene and early zygotene stages, reduction of RAD51 foci at leptotene, and persistence of DNA breaks and unsynapsed chromosomes at pachytene. This finding is consistent with the known function of RAD51C in DSB repair but does not provide any evidence to implicate RAD51C in the late steps of the recombination.
How does an HJ resolution defect result in sister chromatid separation?
The broken chromosomes and aneuploidy observed in Rad51c mutant oocytes are consistent with RAD51C playing a role in HJ resolution. One can expect chromosomes to break if the bivalents do not separate in the absence of HJ resolution. Similarly, it is possible that bivalents can go to the same pole if they remain attached. However, in the Rad51c mutant oocytes, these phenotypes were not frequently observed. The most predominant phenotype displayed by the majority of chromosomes was PSSC, a typical characteristic of a defect in sister chromatid cohesion . So, how can an HJ resolution defect result in this phenotype? Coincidently, a Chinese hamster ovary cell line lacking RAD51C was also reported to exhibit a PSSC defect . Together, these findings raised the question of whether RAD51C may indeed be involved in sister chromatid cohesion. Investigation into a possible role for RAD51C as a cohesin by testing its physical interaction with known cohesins, examining the effect of the loss of RAD51C on the localization of other cohesins on meiotic chromosomes, and electron-microscopic analysis of synapsed chromosomes in mutant spermatocytes yielded no supporting data (Kuznetsov and Sharan, unpublished observation).
Although these possibilities remain to be tested, a genetic evidence reported earlier was used to support this hypothesis . Koehler et al. have shown that, in mouse oocytes, segregation of dicentric chromosomes very frequently (>90%) results in PSSC . They proposed that the physical strain exerted on the homologous centromeres of the dicentric chromatid by the poleward microtubules can result in the PSSC cohesion. Kuznetsov et al. have suggested that unresolved chromosomes and dicentric chromosomes are likely to experience a similar mechanical stress at the centromere during anaphase I and therefore have a similar fate . The processing of dicentric chromosomes is sexually dimorphic and so far has been reported only in mouse and human oocytes. In other organisms, such as maize and flies, such dicentric chromosomes are known to undergo a "bridge-fusion-breakage" cycle [59, 60]. Why dicentric chromosomes have a different fate in mice and human oocytes is currently not understood. Interestingly, some of the spermatocytes from Rad51c mutant infertile males that progressed to metaphase II exhibited chromosomes with broken centromeres, but none showed any sister chromatid cohesion defect, which is consistent with the sexually dimorphic behavior of dicentric chromosomes.
In general, resolution of recombination intermediates in meiosis appears to be tightly linked to sister chromatid cohesion. The condensin-dependent removal of cohesin from the chromosome arms is required for efficient homolog separation in meiosis . At the same time, the condensin – polo-like kinase axis is dispensable for cohesin removal in mitosis . It is not clear how RAD51C might be involved in this particular process and whether it could explain the PSSC phenotype of the RAD51C-deficient mouse oocytes. However, it is intriguing that cohesins and RAD51C are now associated with the resolution of recombination intermediates after previously being independently implicated in the homologous recombination process .
Three years since the initial report showing a role for RAD51C in HJ resolution in mammalian cells, are we any closer to resolving the biological function of RAD51C? In spite of all the biochemical experiments and examination of loss-of-function mutations in Drosophila, Arabidopsis, and mice, the late function in HJ resolution remains to be unequivocally demonstrated. The model to explain the phenotype of Rad51c mutant oocytes at metaphase II is intriguing but needs to be validated. It will be fascinating to directly observe the oocytes undergoing in vitro maturation by time lapse imaging to visualize the bivalents being pulled to opposite poles but remaining attached at the site of the crossover by chiasmata-like structures during anaphase I. Also, it will be interesting to examine the fate of shugoshin and cohesins on the centromeres that have undergone precocious separation. An alternative approach may be to bypass the early meiotic arrest during male meiosis by using a conditional Rad51c allele and generating appropriate meiosis-specific Cre transgenic lines. This approach may provide a more convincing phenotype and help explain the late role of RAD51C in homologous recombination. Similar studies on XRCC3 in meiotic recombination may also provide valuable clues.
The authors thank Drs. Stephen West and Yilun Liu for critical review of the manuscript and Allen Kane of the Publication Department for the illustrations.
- Brugmans L, Kanaar R, Essers J: Analysis of DNA double-strand break repair pathways in mice. Mutat Res 2007, 614: 95–108.PubMedView ArticleGoogle Scholar
- Holliday R: A mechanism for gene conversion in fungi. Genet Res 1964, 5: 282–304.View ArticleGoogle Scholar
- Liu Y, West SC: Happy Hollidays: 40th anniversary of the Holliday junction. Nat Rev Mol Cell Biol 2004, 5: 937–944. 10.1038/nrm1502PubMedView ArticleGoogle Scholar
- Mizuuchi K, Kemper B, Hays J, Weisberg RA: T4 endonuclease VII cleaves holliday structures. Cell 1982, 29: 357–365. 10.1016/0092-8674(82)90152-0PubMedView ArticleGoogle Scholar
- Dunderdale HJ, Benson FE, Parsons CA, Sharples GJ, Lloyd RG, West SC: Formation and resolution of recombination intermediates by E. coli RecA and RuvC proteins. Nature 1991, 354: 506–510. 10.1038/354506a0PubMedView ArticleGoogle Scholar
- Iwasaki H, Takahagi M, Shiba T, Nakata A, Shinagawa H: Escherichia coli RuvC protein is an endonuclease that resolves the Holliday structure. Embo J 1991, 10: 4381–4389.PubMed CentralPubMedGoogle Scholar
- West SC: Processing of recombination intermediates by the RuvABC proteins. Annu Rev Genet 1997, 31: 213–244. 10.1146/annurev.genet.31.1.213PubMedView ArticleGoogle Scholar
- Sharples GJ: The X philes: structure-specific endonucleases that resolve Holliday junctions. Mol Microbiol 2001, 39: 823–834. 10.1046/j.1365-2958.2001.02284.xPubMedView ArticleGoogle Scholar
- Kleff S, Kemper B, Sternglanz R: Identification and characterization of yeast mutants and the gene for a cruciform cutting endonuclease. Embo J 1992, 11: 699–704.PubMed CentralPubMedGoogle Scholar
- Bidnenko E, Ehrlich SD, Chopin MC: Lactococcus lactis phage operon coding for an endonuclease homologous to RuvC. Mol Microbiol 1998, 28: 823–834. 10.1046/j.1365-2958.1998.00845.xPubMedView ArticleGoogle Scholar
- Garcia AD, Aravind L, Koonin EV, Moss B: Bacterial-type DNA holliday junction resolvases in eukaryotic viruses. Proc Natl Acad Sci U S A 2000, 97: 8926–8931. 10.1073/pnas.150238697PubMed CentralPubMedView ArticleGoogle Scholar
- Dickie P, McFadden G, Morgan AR: The site-specific cleavage of synthetic Holliday junction analogs and related branched DNA structures by bacteriophage T7 endonuclease I. J Biol Chem 1987, 262: 14826–14836.PubMedGoogle Scholar
- Mahdi AA, Sharples GJ, Mandal TN, Lloyd RG: Holliday junction resolvases encoded by homologous rusA genes in Escherichia coli K-12 and phage 82. J Mol Biol 1996, 257: 561–573. 10.1006/jmbi.1996.0185PubMedView ArticleGoogle Scholar
- Komori K, Sakae S, Shinagawa H, Morikawa K, Ishino Y: A Holliday junction resolvase from Pyrococcus furiosus: functional similarity to Escherichia coli RuvC provides evidence for conserved mechanism of homologous recombination in Bacteria, Eukarya, and Archaea. Proc Natl Acad Sci U S A 1999, 96: 8873–8878. 10.1073/pnas.96.16.8873PubMed CentralPubMedView ArticleGoogle Scholar
- Kvaratskhelia M, White MF: An archaeal Holliday junction resolving enzyme from Sulfolobus solfataricus exhibits unique properties. J Mol Biol 2000, 295: 193–202. 10.1006/jmbi.1999.3363PubMedView ArticleGoogle Scholar
- Kvaratskhelia M, White MF: Two Holliday junction resolving enzymes in Sulfolobus solfataricus. J Mol Biol 2000, 297: 923–932. 10.1006/jmbi.2000.3624PubMedView ArticleGoogle Scholar
- Lockshon D, Zweifel SG, Freeman-Cook LL, Lorimer HE, Brewer BJ, Fangman WL: A role for recombination junctions in the segregation of mitochondrial DNA in yeast. Cell 1995, 81: 947–955. 10.1016/0092-8674(95)90014-4PubMedView ArticleGoogle Scholar
- Boddy MN, Gaillard PH, McDonald WH, Shanahan P, Yates JR 3rd, Russell P: Mus81-Eme1 are essential components of a Holliday junction resolvase. Cell 2001, 107: 537–548. 10.1016/S0092-8674(01)00536-0PubMedView ArticleGoogle Scholar
- Osman F, Dixon J, Doe CL, Whitby MC: Generating crossovers by resolution of nicked Holliday junctions: a role for Mus81-Eme1 in meiosis. Mol Cell 2003, 12: 761–774. 10.1016/S1097-2765(03)00343-5PubMedView ArticleGoogle Scholar
- Interthal H, Heyer WD: MUS81 encodes a novel helix-hairpin-helix protein involved in the response to UV- and methylation-induced DNA damage in Saccharomyces cerevisiae. Mol Gen Genet 2000, 263: 812–827. 10.1007/s004380000241PubMedView ArticleGoogle Scholar
- de los Santos T, Hunter N, Lee C, Larkin B, Loidl J, Hollingsworth NM: The Mus81/Mms4 endonuclease acts independently of double-Holliday junction resolution to promote a distinct subset of crossovers during meiosis in budding yeast. Genetics 2003, 164: 81–94.PubMed CentralPubMedGoogle Scholar
- de los Santos T, Loidl J, Larkin B, Hollingsworth NM: A role for MMS4 in the processing of recombination intermediates during meiosis in Saccharomyces cerevisiae. Genetics 2001, 159: 1511–1525.PubMed CentralPubMedGoogle Scholar
- Hartung F, Suer S, Bergmann T, Puchta H: The role of AtMUS81 in DNA repair and its genetic interaction with the helicase AtRecQ4A. Nucleic Acids Res 2006, 34: 4438–4448. 10.1093/nar/gkl576PubMed CentralPubMedView ArticleGoogle Scholar
- Chen XB, Melchionna R, Denis CM, Gaillard PH, Blasina A, Van de Weyer I, Boddy MN, Russell P, Vialard J, McGowan CH: Human Mus81-associated endonuclease cleaves Holliday junctions in vitro. Mol Cell 2001, 8: 1117–1127. 10.1016/S1097-2765(01)00375-6PubMedView ArticleGoogle Scholar
- Ciccia A, Constantinou A, West SC: Identification and characterization of the human mus81-eme1 endonuclease. J Biol Chem 2003, 278: 25172–25178. 10.1074/jbc.M302882200PubMedView ArticleGoogle Scholar
- Haber JE, Heyer WD: The fuss about Mus81. Cell 2001, 107: 551–554. 10.1016/S0092-8674(01)00593-1PubMedView ArticleGoogle Scholar
- McPherson JP, Lemmers B, Chahwan R, Pamidi A, Migon E, Matysiak-Zablocki E, Moynahan ME, Essers J, Hanada K, Poonepalli A, Sanchez-Sweatman O, Khokha R, Kanaar R, Jasin M, Hande MP, Hakem R: Involvement of mammalian Mus81 in genome integrity and tumor suppression. Science 2004, 304: 1822–1826. 10.1126/science.1094557PubMedView ArticleGoogle Scholar
- Dendouga N, Gao H, Moechars D, Janicot M, Vialard J, McGowan CH: Disruption of murine Mus81 increases genomic instability and DNA damage sensitivity but does not promote tumorigenesis. Mol Cell Biol 2005, 25: 7569–7579. 10.1128/MCB.25.17.7569-7579.2005PubMed CentralPubMedView ArticleGoogle Scholar
- Constantinou A, Chen XB, McGowan CH, West SC: Holliday junction resolution in human cells: two junction endonucleases with distinct substrate specificities. Embo J 2002, 21: 5577–5585. 10.1093/emboj/cdf554PubMed CentralPubMedView ArticleGoogle Scholar
- Liu Y, Masson JY, Shah R, O'Regan P, West SC: RAD51C is required for Holliday junction processing in mammalian cells. Science 2004, 303: 243–246. 10.1126/science.1093037PubMedView ArticleGoogle Scholar
- Kawabata M, Kawabata T, Nishibori M: Role of recA/RAD51 family proteins in mammals. Acta Med Okayama 2005, 59: 1–9.PubMedGoogle Scholar
- Miller KA, Sawicka D, Barsky D, Albala JS: Domain mapping of the Rad51 paralog protein complexes. Nucleic Acids Res 2004, 32: 169–178. 10.1093/nar/gkg925PubMed CentralPubMedView ArticleGoogle Scholar
- Shinohara A, Shinohara M: Roles of RecA homologues Rad51 and Dmc1 during meiotic recombination. Cytogenet Genome Res 2004, 107: 201–207. 10.1159/000080598PubMedView ArticleGoogle Scholar
- Masson JY, Tarsounas MC, Stasiak AZ, Stasiak A, Shah R, McIlwraith MJ, Benson FE, West SC: Identification and purification of two distinct complexes containing the five RAD51 paralogs. Genes Dev 2001, 15: 3296–3307. 10.1101/gad.947001PubMed CentralPubMedView ArticleGoogle Scholar
- Takata M, Sasaki MS, Tachiiri S, Fukushima T, Sonoda E, Schild D, Thompson LH, Takeda S: Chromosome instability and defective recombinational repair in knockout mutants of the five Rad51 paralogs. Mol Cell Biol 2001, 21: 2858–2866. 10.1128/MCB.21.8.2858-2866.2001PubMed CentralPubMedView ArticleGoogle Scholar
- Yonetani Y, Hochegger H, Sonoda E, Shinya S, Yoshikawa H, Takeda S, Yamazoe M: Differential and collaborative actions of Rad51 paralog proteins in cellular response to DNA damage. Nucleic Acids Res 2005, 33: 4544–4552. 10.1093/nar/gki766PubMed CentralPubMedView ArticleGoogle Scholar
- Deans B, Griffin CS, Maconochie M, Thacker J: Xrcc2 is required for genetic stability, embryonic neurogenesis and viability in mice. Embo J 2000, 19: 6675–6685. 10.1093/emboj/19.24.6675PubMed CentralPubMedView ArticleGoogle Scholar
- Pittman DL, Schimenti JC: Midgestation lethality in mice deficient for the RecA-related gene, Rad51d/Rad51l3. Genesis 2000, 26: 167–173. 10.1002/(SICI)1526-968X(200003)26:3<167::AID-GENE1>3.0.CO;2-MPubMedView ArticleGoogle Scholar
- Shu Z, Smith S, Wang L, Rice MC, Kmiec EB: Disruption of muREC2/RAD51L1 in mice results in early embryonic lethality which can Be partially rescued in a p53(-/-) background. Mol Cell Biol 1999, 19: 8686–8693.PubMed CentralPubMedView ArticleGoogle Scholar
- Bleuyard JY, Gallego ME, Savigny F, White CI: Differing requirements for the Arabidopsis Rad51 paralogs in meiosis and DNA repair. Plant J 2005, 41: 533–545. 10.1111/j.1365-313X.2004.02318.xPubMedView ArticleGoogle Scholar
- Lio YC, Schild D, Brenneman MA, Redpath JL, Chen DJ: Human Rad51C deficiency destabilizes XRCC3, impairs recombination, and radiosensitizes S/G2-phase cells. J Biol Chem 2004, 279: 42313–42320. 10.1074/jbc.M405212200PubMedView ArticleGoogle Scholar
- Liu Y, Tarsounas M, O'Regan P, West SC: Role of RAD51C and XRCC3 in genetic recombination and DNA repair. J Biol Chem 2007, 282: 1973–1979. 10.1074/jbc.M609066200PubMedView ArticleGoogle Scholar
- Kuznetsov S, Pellegrini M, Shuda K, Fernandez-Capetillo O, Liu Y, Martin BK, Burkett S, Southon E, Pati D, Tessarollo L, West SC, Donovan PJ, Nussenzweig A, Sharan SK: RAD51C deficiency in mice results in early prophase I arrest in males and sister chromatid separation at metaphase II in females. J Cell Biol 2007, 176: 581–592. 10.1083/jcb.200608130PubMed CentralPubMedView ArticleGoogle Scholar
- Baker SM, Plug AW, Prolla TA, Bronner CE, Harris AC, Yao X, Christie DM, Monell C, Arnheim N, Bradley A, Ashley T, Liskay RM: Involvement of mouse Mlh1 in DNA mismatch repair and meiotic crossing over. Nat Genet 1996, 13: 336–342. 10.1038/ng0796-336PubMedView ArticleGoogle Scholar
- Abdu U, Gonzalez-Reyes A, Ghabrial A, Schupbach T: The Drosophila spn-D gene encodes a RAD51C-like protein that is required exclusively during meiosis. Genetics 2003, 165: 197–204.PubMed CentralPubMedGoogle Scholar
- Li W, Yang X, Lin Z, Timofejeva L, Xiao R, Makaroff CA, Ma H: The AtRAD51C Gene Is Required for Normal Meiotic Chromosome Synapsis and Double-Stranded Break Repair in Arabidopsis. Plant Physiol 2005 , 138: 965–976. 10.1104/pp.104.058347PubMed CentralPubMedView ArticleGoogle Scholar
- Libby BJ, De La Fuente R, O'Brien MJ, Wigglesworth K, Cobb J, Inselman A, Eaker S, Handel MA, Eppig JJ, Schimenti JC: The mouse meiotic mutation mei1 disrupts chromosome synapsis with sexually dimorphic consequences for meiotic progression. Dev Biol 2002, 242: 174–187. 10.1006/dbio.2001.0535PubMedView ArticleGoogle Scholar
- Sharan SK, Pyle A, Coppola V, Babus J, Swaminathan S, Benedict J, Swing D, Martin BK, Tessarollo L, Evans JP, Flaws JA, Handel MA: BRCA2 deficiency in mice leads to meiotic impairment and infertility. Development 2004, 131: 131–142. 10.1242/dev.00888PubMedView ArticleGoogle Scholar
- Revenkova E, Eijpe M, Heyting C, Hodges CA, Hunt PA, Liebe B, Scherthan H, Jessberger R: Cohesin SMC1 beta is required for meiotic chromosome dynamics, sister chromatid cohesion and DNA recombination. Nat Cell Biol 2004, 6: 555–562. 10.1038/ncb1135PubMedView ArticleGoogle Scholar
- Godthelp BC, Wiegant WW, van Duijn-Goedhart A, Scharer OD, van Buul PP, Kanaar R, Zdzienicka MZ: Mammalian Rad51C contributes to DNA cross-link resistance, sister chromatid cohesion and genomic stability. Nucleic Acids Res 2002, 30: 2172–2182. 10.1093/nar/30.10.2172PubMed CentralPubMedView ArticleGoogle Scholar
- Marston AL, Amon A: Meiosis: cell-cycle controls shuffle and deal. Nat Rev Mol Cell Biol 2004, 5: 983–997. 10.1038/nrm1526PubMedView ArticleGoogle Scholar
- Watanabe Y: Shugoshin: guardian spirit at the centromere. Curr Opin Cell Biol 2005, 17: 590–595. 10.1016/j.ceb.2005.10.003PubMedView ArticleGoogle Scholar
- Watanabe Y: Sister chromatid cohesion along arms and at centromeres. Trends Genet 2005, 21: 405–412. 10.1016/j.tig.2005.05.009PubMedView ArticleGoogle Scholar
- Wang X, Dai W: Shugoshin, a guardian for sister chromatid segregation. Exp Cell Res 2005, 310: 1–9. 10.1016/j.yexcr.2005.07.018PubMedView ArticleGoogle Scholar
- Goulding SE, Earnshaw WC: Shugoshin: a centromeric guardian senses tension. Bioessays 2005, 27: 588–591. 10.1002/bies.20240PubMedView ArticleGoogle Scholar
- Indjeian VB, Stern BM, Murray AW: The centromeric protein Sgo1 is required to sense lack of tension on mitotic chromosomes. Science 2005, 307: 130–133. 10.1126/science.1101366PubMedView ArticleGoogle Scholar
- Eaker S, Pyle A, Cobb J, Handel MA: Evidence for meiotic spindle checkpoint from analysis of spermatocytes from Robertsonian-chromosome heterozygous mice. J Cell Sci 2001, 114: 2953–2965.PubMedGoogle Scholar
- Koehler KE, Millie EA, Cherry JP, Burgoyne PS, Evans EP, Hunt PA, Hassold TJ: Sex-specific differences in meiotic chromosome segregation revealed by dicentric bridge resolution in mice. Genetics 2002, 162: 1367–1379.PubMed CentralPubMedGoogle Scholar
- Novitski E: Genetic measures of centromere activity in Drosophila melanogaster. J Cell Physiol Suppl 1955, 45: 151–169.PubMedView ArticleGoogle Scholar
- McClintock B: The Fusion of Broken Ends of Chromosomes Following Nuclear Fusion. Proc Natl Acad Sci U S A 1942, 28: 458–463. 10.1073/pnas.28.11.458PubMed CentralPubMedView ArticleGoogle Scholar
- Yu HG, Koshland D: Chromosome morphogenesis: condensin-dependent cohesin removal during meiosis. Cell 2005, 123: 397–407. 10.1016/j.cell.2005.09.014PubMedView ArticleGoogle Scholar
- Hauf S, Roitinger E, Koch B, Dittrich CM, Mechtler K, Peters JM: Dissociation of cohesin from chromosome arms and loss of arm cohesion during early mitosis depends on phosphorylation of SA2. PLoS Biol 2005, 3: e69. 10.1371/journal.pbio.0030069PubMed CentralPubMedView ArticleGoogle Scholar
- Kim JS, Krasieva TB, LaMorte V, Taylor AM, Yokomori K: Specific recruitment of human cohesin to laser-induced DNA damage. J Biol Chem 2002, 277: 45149–45153. 10.1074/jbc.M209123200PubMedView ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.