Rad51 Paralog Complexes BCDX2 and CX3 Act at Different Stages in the BRCA1-BRCA2-Dependent Homologous Recombination Pathway

Chun, Jarin; Buechelmaier, Erika S.; Powell, Simon N.

doi:10.1128/mcb.00465-12

Cited by 182 publications

(200 citation statements)

References 41 publications

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“…Data to support this include binding of CX3 and BCDX2 ring structures to Holliday junctions and Holliday junction branch migration and resolution activities by these complexes in vitro (211,212). Evidence for BCDX2 acting upstream and CX3 downstream of RAD51 recruitment has been brought recently by RNA interference (RNAi) depletion studies (213).…”

Section: Homologous Recombinationmentioning

confidence: 90%

DNA Repair Pathways in Trypanosomatids: from DNA Repair to Drug Resistance

Genois

Paquet

Laffitte

et al. 2014

Microbiol Mol Biol Rev

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SUMMARY All living organisms are continuously faced with endogenous or exogenous stress conditions affecting genome stability. DNA repair pathways act as a defense mechanism, which is essential to maintain DNA integrity. There is much to learn about the regulation and functions of these mechanisms, not only in human cells but also equally in divergent organisms. In trypanosomatids, DNA repair pathways protect the genome against mutations but also act as an adaptive mechanism to promote drug resistance. In this review, we scrutinize the molecular mechanisms and DNA repair pathways which are conserved in trypanosomatids. The recent advances made by the genome consortiums reveal the complete genomic sequences of several pathogens. Therefore, using bioinformatics and genomic sequences, we analyze the conservation of DNA repair proteins and their key protein motifs in trypanosomatids. We thus present a comprehensive view of DNA repair processes in trypanosomatids at the crossroads of DNA repair and drug resistance.

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Section: Homologous Recombinationmentioning

confidence: 90%

DNA Repair Pathways in Trypanosomatids: from DNA Repair to Drug Resistance

Genois

Paquet

Laffitte

et al. 2014

Microbiol Mol Biol Rev

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“…7 RAD51D protein forms a complex with RAD51B, RAD51C and XRCC2 (BCDX2 complex), 8 which is responsible for RAD51 recruitment or stabilization at DNA damage sites. 9 Additionally, it has been described that RAD51D plays a role in telomere protection against attrition and chromosome fusion. 10 Loveday et al 6 identified inactivating mutations in RAD51D in eight of the 911 British cases with a familial history of BC/ OC (0.88%) and in one of the 1,060 British controls (0.09%).…”

Section: -5mentioning

confidence: 99%

About 1% of the breast and ovarian Spanish families testing negative for BRCA1 and BRCA2 are carriers of RAD51D pathogenic variants

Gutiérrez‐Enríquez

Bonache

Garibay

et al. 2013

Intl Journal of Cancer

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RAD51D mutations have been recently identified in breast (BC) and ovarian cancer (OC) families. Although an etiological role in OC appears to be present, the association of RAD51D mutations and BC risk is more unclear. We aimed to determine the prevalence of germline RAD51D mutations in Spanish BC/OC families negative for BRCA1/BRCA2 mutations. We analyzed 842 index patients: 491 from BC/OC families, 171 BC families, 51 OC families and 129 patients without family history but with early-onset BC or OC or metachronous BC and OC. Mutation detection was performed with high-resolution melting, denaturing high-performance liquid chromatography or Sanger sequencing. Three mutations were found in four families with BC and OC cases (0.82%). Two were novel: c.1A>T (p.Met1?) and c.66712_667123del, leading to the exon 7 skipping and one previously described: c.674C>T (p.Arg232*). All were present in BC/OC families with only one OC. The c.66712_667123del cosegregated in the family with one early-onset BC and two bilateral BC cases. We also identified the c.629C>T (p.Ala210Val) variant, which was predicted in silico to be potentially pathogenic. About 1% of the BC and OC Spanish families negative for BRCA1/BRCA2 are carriers of RAD51D mutations. The presence of several BC mutation carriers, albeit in the context of familial OC, suggests an increased risk for BC, which should be taken into account in the follow-up and early detection measures. RAD51D testing should be considered in clinical setting for families with BC and OC, irrespective of the number of OC cases in the family.

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“…Notably, RAD51 paralogs have been recently shown to participate in BRCA1/2-mediated HR (14,15). However, BRCA2 has been implicated in replication fork stabilization but not its restart (44,45).…”

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confidence: 99%

ATM- and ATR-Mediated Phosphorylation of XRCC3 Regulates DNA Double-Strand Break-Induced Checkpoint Activation and Repair

Somyajit

Basavaraju

Scully

et al. 2013

Molecular and Cellular Biology

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The RAD51 paralogs XRCC3 and RAD51C have been implicated in homologous recombination (HR) and DNA damage responses. However, the molecular mechanism(s) by which these paralogs regulate HR and DNA damage signaling remains obscure. Here, we show that an SQ motif serine 225 in XRCC3 is phosphorylated by ATR kinase in an ATM signaling pathway. We find that RAD51C but not XRCC2 is essential for XRCC3 phosphorylation, and this modification follows end resection and is specific to S and G 2 phases. XRCC3 phosphorylation is required for chromatin loading of RAD51 and HR-mediated repair of double-strand breaks (DSBs). Notably, in response to DSBs, XRCC3 participates in the intra-S-phase checkpoint following its phosphorylation and in the G 2 /M checkpoint independently of its phosphorylation. Strikingly, we find that XRCC3 distinctly regulates recovery of stalled and collapsed replication forks such that phosphorylation is required for the HR-mediated recovery of collapsed replication forks but is dispensable for the restart of stalled replication forks. Together, these findings suggest that XRCC3 is a new player in the ATM/ATR-induced DNA damage responses to control checkpoint and HR-mediated repair.T he genome of every living organism is susceptible to various types of DNA damage. Cells have evolved with DNA damage surveillance mechanisms to activate cell cycle checkpoints and DNA repair processes to preserve the integrity of the genome (1-6). The DNA damage response (DDR) pathways are primarily regulated by ataxia telangiectasia mutated (ATM) and ATM-and Rad3-related (ATR) kinases, which are members of the phosphatidylinositol 3-kinase-like kinase (PIKK) family. ATM is recruited to double-strand breaks (DSBs) in part by the MRN (MRE11-RAD50-NBS1) complex, whereas ATR-with its regulator ATRIP (ATR-interacting protein)-senses replication protein A (RPA)-coated single-stranded DNA (ssDNA) that is generated from stalled replication forks or from the processing of DSBs (7-10). When activated, ATM and ATR phosphorylate various substrates at their serine and/or threonine residues within the conserved S/TQ motif, thereby inducing DDR to pause cell cycle progression and activate DNA repair processes (11).The RAD51 recombinase plays a central role in the homologous recombination (HR)-mediated repair of DSBs, daughterstrand gaps (DSGs), and interstrand cross-links (ICLs) (10, 12). Mammals possess five RAD51 paralogs-RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3-which have been implicated in RAD51-mediated HR. RAD51 paralog-deficient cells exhibit sensitivity to DNA damage, spontaneous chromosomal aberrations, reduced RAD51 nuclear focus formation, and decreased HR (12, 13). These paralogs act in the BRCA1/2 pathway to control HR (14, 15). The RAD51 paralogs differentially regulate both shortand long-tract gene conversions and have been implicated in the late stages of HR for resolving recombination intermediates (16,17). In addition to HR, RAD51 paralogs have been implicated in chromosome segregation and in the prevention of aberrant...

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Rad51 Paralog Complexes BCDX2 and CX3 Act at Different Stages in the BRCA1-BRCA2-Dependent Homologous Recombination Pathway

Cited by 182 publications

References 41 publications

DNA Repair Pathways in Trypanosomatids: from DNA Repair to Drug Resistance

DNA Repair Pathways in Trypanosomatids: from DNA Repair to Drug Resistance

About 1% of the breast and ovarian Spanish families testing negative for BRCA1 and BRCA2 are carriers of RAD51D pathogenic variants

ATM- and ATR-Mediated Phosphorylation of XRCC3 Regulates DNA Double-Strand Break-Induced Checkpoint Activation and Repair

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