Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway

Kim, Hyungjin; D’Andrea, Alan D.

doi:10.1101/gad.195248.112

Cited by 448 publications

(512 citation statements)

References 187 publications

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“…1), a particularly pernicious lesion, as repair by NHEJ or aEJ/ MMEJ will inevitably lead to genomic rearrangements. Interestingly, the Fanconi pathway (Kim and D'Andrea 2012) appears to be involved in inhibiting NHEJ in S phase (Adamo et al 2010;Pace et al 2010). This activity was unveiled by finding that Caenorhabditis elegans or human FANCD2-deficient cells are substantially suppressed for their interstrand cross-link sensitivity by eliminating NHEJ.…”

Section: Dsb-repair Pathway Choice or How Resection Commits To Hrmentioning

confidence: 99%

Regulation of Recombination and Genomic Maintenance

Heyer

2015

Cold Spring Harb Perspect Biol

104

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Recombination is a central process to stably maintain and transmit a genome through somatic cell divisions and to new generations. Hence, recombination needs to be coordinated with other events occurring on the DNA template, such as DNA replication, transcription, and the specialized chromosomal functions at centromeres and telomeres. Moreover, regulation with respect to the cell-cycle stage is required as much as spatiotemporal coordination within the nuclear volume. These regulatory mechanisms impinge on the DNA substrate through modifications of the chromatin and directly on recombination proteins through a myriad of posttranslational modifications (PTMs) and additional mechanisms. Although recombination is primarily appreciated to maintain genomic stability, the process also contributes to gross chromosomal arrangements and copy-number changes. Hence, the recombination process itself requires quality control to ensure high fidelity and avoid genomic instability. Evidently, recombination and its regulatory processes have significant impact on human disease, specifically cancer and, possibly, neurodegenerative diseases.

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Section: Dsb-repair Pathway Choice or How Resection Commits To Hrmentioning

confidence: 99%

Regulation of Recombination and Genomic Maintenance

Heyer

2015

Cold Spring Harb Perspect Biol

104

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“…15,20,46,47 10 mg of each Ter/HR reporter ROSA26 targeting plasmid was linearized by Kpn I digest and introduced by electroporation to 2 £ 10 7 cells. Cells were seeded on plates prepared previously with puromycin-resistant feeders.…”

Section: Mouse Cell Lines and Cell Culturementioning

confidence: 99%

“…7 The hereditary breast/ovarian cancer predisposition genes, BRCA1 and BRCA2, in concert with other Fanconi anemia genes and other HR genes, have been implicated in regulating HR/SCR in response to replication fork stalling, underscoring the importance of this process for cancer predisposition. [8][9][10] We recently adapted the Escherichia coli Tus/Ter replication fork arrest complex [11][12][13][14] to provoke site-specific replication fork stalling and chromosomal HR in mammalian cells. 15 In E. coli, binding of the monomeric Tus protein to the asymmetrical »23 bp Ter site provokes polar replication fork arrest, depending on whether the replicative helicase DnaB arrives at the non-permissive or permissive end of Ter.…”

Section: Introductionmentioning

confidence: 99%

Spatial separation of replisome arrest sites influences homologous recombination quality at a Tus/Ter-mediated replication fork barrier

Willis

Scully

2016

Cell Cycle

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The Escherichia coli replication fork arrest complex Tus/Ter mediates site-specific replication fork arrest and homologous recombination (HR) on a mammalian chromosome, inducing both conservative "short tract" gene conversion (STGC) and error-prone "long tract" gene conversion (LTGC) products. We showed previously that bidirectional fork arrest is required for the generation of STGC products at Tus/Ter-stalled replication forks and that the HR mediators BRCA1, BRCA2 and Rad51 mediate STGC but suppress LTGC at Tus/Ter-arrested forks. Here, we report the impact of Ter array length on Tus/Ter-induced HR, comparing HR reporters containing arrays of 6, 9, 15 or 21 Ter sites-each targeted to the ROSA26 locus of mouse embryonic stem (ES) cells. Increasing Ter copy number within the array beyond 6 did not affect the magnitude of Tus/Ter-induced HR but biased HR in favor of LTGC. A "lock"-defective Tus mutant, F140A, known to exhibit higher affinity than wild type (wt)Tus for duplex Ter, reproduced these effects. In contrast, increasing Ter copy number within the array reduced HR induced by the I-SceI homing endonuclease, but produced no consistent bias toward LTGC. Thus, the mechanisms governing HR at Tus/Ter-arrested replication forks are distinct from those governing HR at an enzyme-induced chromosomal double strand break (DSB). We propose that increased spatial separation of the 2 arrested forks encountering an extended Tus/Ter barrier impairs the coordination of DNA ends generated by the processing of the stalled forks, thereby favoring aberrant LTGC over conservative STGC.

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“…10 The USP1 gene encodes a member of the ubiquitin-specific proteases that is a deubiquitinating enzyme (DUB) with His and Cys domains. 11 USP1 has been identified as a key regulator in the DNA repair processes, mainly in the Fanconi anemia pathway and Translesion DNA synthesis by regulating ubiquitination status of FANCD2 and PCNA, 12,13 Mono-ubiquitinated FANCD2 and PCNA serve as a platform to recruit DNA repair proteins to DNA damage sites, [14][15][16] and USP-induced deubiquitination of FANCD2 and PCNA is crucial for the correct function of DNA repair pathway. 17,18 Indeed, Usp1 gene deletion in mice 18 and USP1 inhibition by small molecules displayed chemosensitizing effects against DNA damaging agents, [19][20][21] indicating that USP1 is required for an efficient DNA repair activity.…”

Section: Introductionmentioning

confidence: 99%

A novel role for the deubiquitinase USP1 in the control of centrosome duplication

2016

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Defects in the regulation of centrosome duplication lead to tumorigenesis through abnormal cell division and resulting chromosome missegregation. Therefore, maintenance of accurate centrosome number is critical for cell fate. The deubiquitinating enzyme USP1 plays important roles in DNA repair and cell differentiation. Importantly, increased levels of USP1 are detected in certain types of human cancer, but little is known about the significance of USP1 overexpression in cancer development. Here we show that Usp1 plays a novel role in regulating centrosome duplication. The ectopic expression of wild-type Usp1, but not C90S Usp1 (catalytically inactive mutant form), induced centrosome amplification. Conversely, ablation of Usp1 in mouse embryonic fibroblasts (MEFs) showed a significant delay in centrosome duplication. Moreover, Usp1-induced centrosome amplification caused abnormal mitotic spindles, chromosome missegregation and aneuploidy. Interestingly, loss of inhibitor of DNA binding protein 1 (ID1) suppressed Usp1-induced centrosome amplification. Taken together, our results strongly suggest that Usp1 is involved in the regulation of centrosome duplication, at least in part via ID1, and Usp1 may exert its oncogenic activity, partially through inducing centrosome abnormality.

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Regulation of DNA cross-link repair by the Fanconi anemia/BRCA pathway

Cited by 448 publications

References 187 publications

Regulation of Recombination and Genomic Maintenance

Regulation of Recombination and Genomic Maintenance

Spatial separation of replisome arrest sites influences homologous recombination quality at a Tus/Ter-mediated replication fork barrier

A novel role for the deubiquitinase USP1 in the control of centrosome duplication

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