ATP Hydrolysis by Mammalian RAD51 Has a Key Role during Homology-directed DNA Repair

Stark, Jeremy M.; Hu, Peng; Pierce, Andrew J.; Moynahan, Mary Ellen; Ellis, Nathan A.; Jasin, Maria

doi:10.1074/jbc.m112132200

Cited by 130 publications

(157 citation statements)

References 57 publications

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“…The crystal structure of a BRCA2 BRC4-Rad51 fusion protein indicates that the BRC domain interacts with the core of Rad51 and, by a process of molecular mimicry, prevents the homo-oligomerization of Rad51 [136]. Consistent with this, isolated BRC fragments of BRCA2 inhibit Rad51-mediated strand exchange in vitro and interfere with HR in vivo [135,139]. In contrast, certain combined domains of BRCA2 promote Rad51-mediated strand exchange in vitro, suggesting that there may be intramolecular collaboration between distinct domains of BRCA2 [140,161].…”

Section: Molecular Functions Of Brca1 and Brca2mentioning

confidence: 83%

Minding the gap: The underground functions of BRCA1 and BRCA2 at stalled replication forks

Nagaraju

Scully

2007

DNA Repair

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The hereditary breast and ovarian cancer predisposition genes, BRCA1 and BRCA2, participate in the repair of DNA double strand breaks by homologous recombination. Circumstantial evidence implicates these genes in recombinational responses to DNA polymerase stalling during the S phase of the cell cycle. These responses play a key role in preventing genomic instability and cancer. Here, we review the current literature implicating the BRCA pathway in HR at stalled replication forks and explore the hypothesis that BRCA1 and BRCA2 participate in the recombinational resolution of single stranded DNA lesions termed "daughter strand gaps", generated during replication across a damaged DNA template.

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Section: Molecular Functions Of Brca1 and Brca2mentioning

confidence: 83%

Minding the gap: The underground functions of BRCA1 and BRCA2 at stalled replication forks

Nagaraju

Scully

2007

DNA Repair

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“…71 Homology-mediated DSB repair in mammalian cells requires members of the RAD52 epistasis group. 72 Rad51 is central to most homologous recombination events; Rad51 forms nucleoprotein filaments on ssDNA, and mediates homologous pairing and strand exchange between DNA duplexes, 73,74 although single-strand annealing can be promoted by Rad52 in the absence of Rad51. 75 Whether the homology-mediated events observed here are Rad51 dependent or are sufficiently promoted by the annealing activity of Rad52 is not clear.…”

Section: Discussionmentioning

confidence: 99%

Therapy-related acute myeloid leukemia–like MLL rearrangements are induced by etoposide in primary human CD34+ cells and remain stable after clonal expansion

Libura

Slater

Felix

et al. 2005

Blood

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Rearrangements involving the MLL gene on chromosome band 11q23 are a hallmark of therapy-related acute myeloid leukemias following treatment with topoisomerase II poisons including etoposide. Therapy-related and de novo genomic translocation breakpoints cluster within a well-characterized 8.3-kb fragment of MLL. Repair of etoposidestabilized DNA topoisomerase II covalent complexes may initiate MLL rearrangements observed in patients. We used a culture system of primary human hematopoietic CD34 ؉ cells and inverse polymerase chain reaction to characterize the spectrum of stable genomic rearrangements promoted by etoposide exposure originating within an MLL translocation hotspot in therapy-related leukemia. Alterations to the region were observed at a readily detectable frequency in etoposidetreated cells. Illegitimate repair events after minimal repair included MLL tandem duplications and translocations, with minor populations of deletions or insertions. In stably repaired cells that proliferated for 10 to 14 days, the significant majority of illegitimate events were MLL IntroductionGenome integrity is controlled by multiple damage surveillance pathways, cell-cycle checkpoints, and repair mechanisms. [1][2][3] Despite these safeguards, illegitimate repair of chromosomal doublestrand breaks (DSBs), such as those produced by chemotherapy agents that target topoisomerase II (topo II), can promote chromosomal rearrangements and, ultimately, tumorigenesis. Topo II is an essential cellular enzyme that catalyzes changes in DNA topology via its cleavage-religation equilibrium. Topo II-targeted drugs that are poisons of this enzyme stabilize topo II-DNA covalent complexes, most often by decreasing the rate of religation in a dose-dependent manner. Disruption of the cleavage-religation reaction results in accumulation of DSBs, p53 activation, and induction of apoptosis or repair. 4,5 Chromosomal DSBs are potent inducers of recombination, stimulating the exchange of homologous sequences between 2 DNA duplexes 1000-fold 6-8 not only between sister chromatids, but also between homologs, and sequence repeats on heterologous chromosomes. 9-12 DSBs may be repaired by homologous recombination or nonhomologous end joining (NHEJ), and both repair mechanisms have been associated with chromosomal translocations, a hallmark of leukemias, lymphomas, and soft-tissue sarcomas. [13][14][15] There is clear evidence that exposure to chemotherapy or irradiation can result in subsequent development of therapy-related leukemias, which occur in 1% to 15% of patients exposed to DNA-damaging agents in anticancer regimens. 16,17 Exposure to topo II poisons such as etoposide is predominantly associated with therapy-related leukemias characterized by rearrangements of the MLL gene on chromosome band 11q23. 16 MLL spans 100 kb, encodes a 430-kDa protein homologous to the Drosophila trithorax gene, and has important functions in embryogenesis and hematopoiesis. 18,19 Mixed-lineage leukemia (MLL) is a critical transcriptional regulator and numerous tr...

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“…To confirm that GFPϩ cells had undergone short-track gene conversion, genomic DNA was isolated from FACS-sorted GFPϩ cells, then digested with SalI, HindIII, and I-SceI or Bcg1, and then probed for the I-SceI-GFP as described (17). Global DSB repair was measured by a PCR-based assay as described in detail (18). Briefly, genomic DNA was isolated from DRAA8-MYCER cells that had been either not transfected or transfected with I-SceI and untreated or treated with E 2 .…”

Section: Methodsmentioning

confidence: 99%

Defective double-strand DNA break repair and chromosomal translocations by MYC overexpression

Karlsson

Deb-Basu

Cherry

et al. 2003

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

148

122

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DNA repair mechanisms are essential for the maintenance of genomic integrity. Disruption of gene products responsible for DNA repair can result in chromosomal damage. Improperly repaired chromosomal damage can result in the loss of chromosomes or the generation of chromosomal deletions or translocations, which can lead to tumorigenesis. The MYC protooncogene is a transcription factor whose overexpression is frequently associated with human neoplasia. MYC has not been previously implicated in a role in DNA repair. Here we report that the overexpression of MYC disrupts the repair of double-strand DNA breaks, resulting in a several-magnitude increase in chromosomal breaks and translocations. We found that MYC inhibited the repair of ␥ irradiation DNA breaks in normal human cells and blocked the repair of a single double-strand break engineered to occur in an immortal cell line. By spectral karyotypic analysis, we found that MYC even within one cell division cycle resulted in a several-magnitude increase in the frequency of chromosomal breaks and translocations in normal human cells. Hence, MYC overexpression may be a previously undescribed example of a dominant mutator that may fuel tumorigenesis by inducing chromosomal damage.M any genes have been identified that are responsible for repairing DNA breaks and preserving chromosomal integrity (1-3). The loss of function of some of these genes can result in widespread chromosomal damage and contribute to tumorigenesis (4-6). In mammalian cells, double-strand DNA breaks (DSBs) are repaired by homology-directed recombination (HDR), nonhomologous end joining (NHEJ), and singlestrand annealing (SSA) (7). Defects in any of these repair mechanisms can result in chromosomal breaks, fusions, and translocations (8). Many human cancers exhibit characteristic chromosomal translocations thought to be responsible for tumorigenesis (9). The mechanisms by which these chromosomal translocations occur are not clear.MYC is a protooncogene that normally regulates cellular growth and proliferation and in some contexts induces apoptosis (10-12). MYC overexpression is thought to cause tumorigenesis by promoting unrestrained cellular proliferation and blocking differentiation. MYC overexpression may also contribute to tumorigenesis by inducing genomic destabilization (13-15). The genomic damage induced by MYC can be broadly grouped into two classes of abnormalities. First, overexpression of MYC induces loss of chromosomal integrity associated with chromosomal aberrations such as gene amplifications, double minutes, and fusions. Second, MYC overexpression can cause inappropriate DNA replication, resulting in endoreduplication.We speculated that the former type of genomic abnormalities might be caused by defects in the repair of DSBs. Here we demonstrate that MYC overexpression disrupts the repair of DSBs. Moreover, we show that MYC overexpression in normal human cells results in a several-magnitude increase in chromosomal breaks and translocations. Hence, MYC may be a previously undescribed ...

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ATP Hydrolysis by Mammalian RAD51 Has a Key Role during Homology-directed DNA Repair

Cited by 130 publications

References 57 publications

Minding the gap: The underground functions of BRCA1 and BRCA2 at stalled replication forks

Minding the gap: The underground functions of BRCA1 and BRCA2 at stalled replication forks

Therapy-related acute myeloid leukemia–like MLL rearrangements are induced by etoposide in primary human CD34+ cells and remain stable after clonal expansion

Defective double-strand DNA break repair and chromosomal translocations by MYC overexpression

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