BLM is an early responder to DNA double-strand breaks

Karmakar, Parimal; Seki, Masayuki; Kanamori, Makoto; Hashiguchi, Kazunari; Ohtsuki, Makoto; Murata, Eriko; Inoue, Eri; Tada, Shusuke; Lan, Li; Yasui, Akira; Enomoto, Takemi

doi:10.1016/j.bbrc.2006.07.037

Cited by 61 publications

(35 citation statements)

References 41 publications

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“…However, recent evidence shows that BLM localizes at sites of DSBs almost immediately on breakage (38). Also, BLM is a component of the BASC complex and is phosphorylated by ATM kinase upon DNA damage (39).…”

Section: Discussionmentioning

confidence: 99%

Human exonuclease 1 and BLM helicase interact to resect DNA and initiate DNA repair

Nimonkar

Özsoy

Genschel³

et al. 2008

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

269

236

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The error-free repair of double-stranded DNA breaks by homologous recombination requires processing of broken ends. These processed ends are substrates for assembly of DNA strand exchange proteins that mediate DNA strand invasion. Here, we establish that human BLM helicase, a member of the RecQ family, stimulates the nucleolytic activity of human exonuclease 1 (hExo1), a 5 33 double-stranded DNA exonuclease. The stimulation is specific because other RecQ homologs fail to stimulate hExo1. Stimulation of DNA resection by hExo1 is independent of BLM helicase activity and is, instead, mediated by an interaction between the 2 proteins. Finally, we show that DNA ends resected by hExo1 and BLM are used by human Rad51, but not its yeast or bacterial counterparts, to promote homologous DNA pairing. This in vitro system recapitulates initial steps of homologous recombination and provides biochemical evidence for a role of BLM and Exo1 in the initiation of recombinational DNA repair.Bloom syndrome ͉ Rad51 ͉ recombination ͉ RecQ ͉ DNA pairing H omologous recombination contributes toward the maintenance of genomic integrity by accurately repairing doublestranded DNA (dsDNA) breaks. The recombinational repair of dsDNA breaks (DSBs) proceeds by successive reactions that start with processing of the broken DNA ends to reveal single-stranded DNA (ssDNA) (1). Processing requires the action of a helicase and/or nuclease. The resultant 3Ј-terminated ssDNA is used by a DNA strand exchange protein as the substrate for assembly of the nucleoprotein filament that is the active species in the search for homologous DNA and subsequent DNA pairing. It is unclear which enzymes in eukaryotes resect the DNA break to initiate recombination; however, much is known about the process in bacteria. In Escherichia coli, recombinational DNA repair occurs by either the RecBCD or the RecF pathway (1). RecBCD is a helicase/nuclease that processes dsDNA to produce 3Ј-tailed ssDNA onto which RecA is loaded. In the RecF pathway, a separate helicase and nuclease are used for resection of DSBs and ssDNA-gaps: RecQ, a 3Ј35Ј helicase, and RecJ, a 5Ј33Ј exonuclease (1).

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Section: Discussionmentioning

confidence: 99%

Human exonuclease 1 and BLM helicase interact to resect DNA and initiate DNA repair

Nimonkar

Özsoy

Genschel³

et al. 2008

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

269

236

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“…Upon the occurrence of DNA damage or inhibition of DNA replication, however, BLM dissociates from PML bodies to form nuclear foci, where it colocalizes with other DNA repair proteins, such as RAD51, BRCA1, and the MRE11-RAD50-NBS1 complex (Bischof et al 2001). Consistent with these observations, BLM is recruited to laser-induced DNA doublestrand breaks (DSBs) (Dutertre et al 2000; Karmakar et al 2006).…”

mentioning

confidence: 81%

BLAP18/RMI2, a novel OB-fold-containing protein, is an essential component of the Bloom helicase–double Holliday junction dissolvasome

Singh¹,

Ali²,

Busygina³

et al. 2008

Genes Dev.

191

220

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Bloom Syndrome is an autosomal recessive cancer-prone disorder caused by mutations in the BLM gene. BLM encodes a DNA helicase of the RECQ family, and associates with Topo III␣ and BLAP75/RMI1 (BLAP for BLM-associated polypeptide/RecQ-mediated genome instability) to form the BTB (BLM-Topo III␣-BLAP75/ RMI1) complex. This complex can resolve the double Holliday junction (dHJ), a DNA intermediate generated during homologous recombination, to yield noncrossover recombinants exclusively. This attribute of the BTB complex likely serves to prevent chromosomal aberrations and rearrangements. Here we report the isolation and characterization of a novel member of the BTB complex termed BLAP18/RMI2. BLAP18/RMI2 contains a putative OB-fold domain, and several lines of evidence suggest that it is essential for BTB complex function. First, the majority of BLAP18/RMI2 exists in complex with Topo III␣ and BLAP75/RMI1. Second, depletion of BLAP18/RMI2 results in the destabilization of the BTB complex. Third, BLAP18/RMI2-depleted cells show spontaneous chromosomal breaks and are sensitive to methyl methanesulfonate treatment. Fourth, BLAP18/RMI2 is required to target BLM to chromatin and for the assembly of BLM foci upon hydroxyurea treatment. Finally, BLAP18/RMI2 stimulates the dHJ resolution capability of the BTB complex. Together, these results establish BLAP18/RMI2 as an essential member of the BTB dHJ dissolvasome that is required for the maintenance of a stable genome.[Keywords: RECQ; double Holliday junction; Chromatin; BLAP18/RMI2; BLM] Supplemental material is available at http://www.genesdev.org.

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“…At DSBs in somatic cells, this protein accumulates within 10 seconds upon formation of the break, independent of ATM and NBS1. 110 Mutation of the Blm gene is embryonic lethal, 111 precluding direct analyses of the function of this gene in meiotic recombination.…”

mentioning

confidence: 99%

DNA double strand break repair, chromosome synapsis and transcriptional silencing in meiosis

Inagaki

Schoenmakers²,

Baarends³

2010

Epigenetics

105

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C hromosome pairing and synapsis during meiotic prophase requires the formation and repair of DNA double-strand breaks (DSBs) by the topoisomerase-like enzyme SPO11. Chromosomes, or chromosomal regions, that lack a pairing partner, such as the largely heterologous X and Y chromosomes, show delayed meiotic DSB repair and are transcriptionally silenced. Herein, we review meiosis-specific aspects of DSB repair in relation to homology recognition and meiotic silencing of heterologous regions. We propose a dynamic interplay between progression of synapsis and persistent meiotic DSBs. Signaling from these persistent breaks could inhibit heterologous synapsis and stimulate meiotic silencing of the X and Y chromosomes.

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BLM is an early responder to DNA double-strand breaks

Cited by 61 publications

References 41 publications

Human exonuclease 1 and BLM helicase interact to resect DNA and initiate DNA repair

Human exonuclease 1 and BLM helicase interact to resect DNA and initiate DNA repair

BLAP18/RMI2, a novel OB-fold-containing protein, is an essential component of the Bloom helicase–double Holliday junction dissolvasome

DNA double strand break repair, chromosome synapsis and transcriptional silencing in meiosis

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