Yeast Mre11 and Rad1 Proteins Define a Ku-Independent Mechanism To Repair Double-Strand Breaks Lacking Overlapping End Sequences

Lin, Jia Chin; Kim, Eun Mi; Haber, James E.; Lee, Sang Eun

doi:10.1128/mcb.23.23.8820-8828.2003

Cited by 337 publications

(398 citation statements)

References 75 publications

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“…Our previous studies had suggested that BRCA1 could inhibit the MRN complex, thereby reducing the associated error-prone NHEJ (22). In addition, we also observed that cells with a deficiency of BRCA1 preferred to use microhomologies to mediate endjoining, which was similar to the reported effect of Mre11 in yeast (72). The hypothesis that Mre11 activity is inhibited by wild-type BRCA1 to prevent error-prone end-joining was supported by the biochemical observation that BRCA1 inhibited the nucleolytic activity of Mre11 in vitro (74).…”

Section: Brca1 and Nhejsupporting

confidence: 75%

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The Role of the BRCA1 Tumor Suppressor in DNA Double-Strand Break Repair

Zhang

Powell

2005

Molecular Cancer Research

187

154

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The tumor suppressor gene BRCA1 was cloned in 1994 based on its linkage to early-onset breast and ovarian cancer. Although the BRCA1 protein has been implicated in multiple cellular functions, the precise mechanism that determines its tumor suppressor activity is not defined. Currently, the emerging picture is that BRCA1 plays an important role in maintaining genomic integrity by protecting cells from double-strand breaks (DSB) that arise during DNA replication or after DNA damage. The DSB repair pathways available in mammalian cells are homologous recombination and nonhomologous end-joining. BRCA1 function seems to be regulated by specific phosphorylations in response to DNA damage and we will focus this review on the roles played by BRCA1 in DNA repair and cell cycle checkpoints. Finally, we will explore the idea that tumor suppression by BRCA1 depends on its control of DNA DSB repair, resulting in the promotion of error-free and the inhibition of error-prone recombinational repair.

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Section: Brca1 and Nhejsupporting

confidence: 75%

“…In addition to error-free NHEJ, evidence from both yeast and mammalian cells strongly supports the notion that Kuindependent NHEJ is an error-prone process (69)(70)(71)(72). BRCA1 may also regulate error-prone end-joining: BRCA1 inactivation was associated with large deletions at the site of the DSB (63).…”

Section: Brca1 and Nhejmentioning

confidence: 65%

The Role of the BRCA1 Tumor Suppressor in DNA Double-Strand Break Repair

Zhang

Powell

2005

Molecular Cancer Research

187

154

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“…29 Another mechanism could be microhomology-mediated end-joining (MMEJ), but normally a longer stretch of microhomology (5-25 bp) is required for MMEJ to occur. 30,31 A total of 435 different sequence variants in USH2A have been registered in HGMD Professional (August, 2014). The majority, 450%, consists of missense or nonsense variants, but gross deletions, duplications or complex rearrangements have also been identified and represent about 5% of the variants.…”

Section: Disussionmentioning

confidence: 99%

Partial USH2A deletions contribute to Usher syndrome in Denmark

et al. 2015

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Usher syndrome is an autosomal recessive disorder characterized by congenital hearing impairment, progressive visual loss owing to retinitis pigmentosa and in some cases vestibular dysfunction. Usher syndrome is divided into three subtypes, USH1, USH2 and USH3. Twelve loci and eleven genes have so far been identified. Duplications and deletions in PCDH15 and USH2A that lead to USH1 and USH2, respectively, have previously been identified in patients from United Kingdom, Spain and Italy. In this study, we investigate the proportion of exon deletions and duplications in PCDH15 and USH2A in 20 USH1 and 30 USH2 patients from Denmark using multiplex ligation-dependent probe amplification (MLPA). Two heterozygous deletions were identified in USH2A, but no deletions or duplications were identified in PCDH15. Next-generation mate-pair sequencing was used to identify the exact breakpoints of the two deletions identified in USH2A. Our results suggest that USH2 is caused by USH2A exon deletions in a small fraction of the patients, whereas deletions or duplications in PCDH15 might be rare in Danish Usher patients.

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“…Similarly, endjoining of blunt-ended linearized plasmids in cells without KU80 involve the resection and annealing of short homologous sequences rather than simply joining the blunt ends (13). An analogous microhomology-mediated endjoining (MMEJ) pathway was seen in budding yeast in the case when the 4-bp protruding chromosome ends, created by a site-specific nuclease, were completely nonhomologous (14). Whereas NHEJ between ends that had even partial complementarity were all Ku-dependent, end-joinings between noncomplementary ends were efficient but Ku-independent.…”

mentioning

confidence: 98%

“…Whether the Rad1-Rad10 homologs XPF-ERCC1 play a similar role in removing the extremities of the 3Ј tails after microhomology mediated annealing, as in yeast, is not known; an intriguing clue comes from the fact that this complex is required in the fusions of telomere sequences that have partially cohesive ends (21). Yeast MMEJ also requires the Mre11-Rad50 complex (14); it will be interesting to see whether these proteins are also required in mammalian cells.…”

mentioning

confidence: 99%