Sharpening the ends for repair: mechanisms and regulation of DNA resection

Paudyal, Sharad C.; You, Zhipeng

doi:10.1093/abbs/gmw043

Cited by 9 publications

(7 citation statements)

References 231 publications

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“…Thus, although MRE11 is important for end resection, it is not essential for this process: processing of HO-induced DSBs ( 41 ) and breaks in both DT40 cell and human TK6 B cells ( 42 ) can be efficiently processed in the absence of MRE11 via nuclease redundancy within each system. NBS1, the eukaryote-specific component, is responsible for binding multiple phosphorylated proteins and recruiting MRE11 and RAD50 to DSB sites ( 43 ) through its interaction with MRE11, CtIP, which is also required for initiating resection, and the ATM kinase ( 44 ). End recognition and DSB processing by MRN is an ATP dependent process: here, ATP binding to RAD50 acts to switch the complex from an open to a closed conformation ( 45 ), which facilitates DSB recognition, tethering and ATM activation ( 45 ).…”

Section: Introductionmentioning

confidence: 99%

The MRN complex promotes DNA repair by homologous recombination and restrains antigenic variation in African trypanosomes

Mehnert

Prorocic

Dujeancourt-Henry

et al. 2021

Nucleic Acids Research

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Homologous recombination dominates as the major form of DNA repair in Trypanosoma brucei, and is especially important for recombination of the subtelomeric variant surface glycoprotein during antigenic variation. RAD50, a component of the MRN complex (MRE11, RAD50, NBS1), is central to homologous recombination through facilitating resection and governing the DNA damage response. The function of RAD50 in trypanosomes is untested. Here we report that RAD50 and MRE11 are required for RAD51-dependent homologous recombination and phosphorylation of histone H2A following a DNA double strand break (DSB), but neither MRE11 nor RAD50 substantially influence DSB resection at a chromosome-internal locus. In addition, we reveal intrinsic separation-of-function between T. brucei RAD50 and MRE11, with only RAD50 suppressing DSB repair using donors with short stretches of homology at a subtelomeric locus, and only MRE11 directing DSB resection at the same locus. Finally, we show that loss of either MRE11 or RAD50 causes a greater diversity of expressed VSG variants following DSB repair. We conclude that MRN promotes stringent homologous recombination at subtelomeric loci and restrains antigenic variation.

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Section: Introductionmentioning

confidence: 99%

The MRN complex promotes DNA repair by homologous recombination and restrains antigenic variation in African trypanosomes

Mehnert

Prorocic

Dujeancourt-Henry

et al. 2021

Nucleic Acids Research

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“…The choice between these repair pathways is dictated by end resection, a DNA processing mechanism that selectively degrades the 5′ strand DNA from the ends to generate long 3′ ssDNA overhangs required for HR in S and G2 phases of the cell cycle. By converting dsDNA ends into ssDNA structures, resection promotes HR and averts NHEJ (11,15–18). DSB resection also controls the checkpoint responses that coordinate DNA repair with other cellular processes such as cell cycle progression and gene expression (19–22).…”

Section: Introductionmentioning

confidence: 99%

Dna2 initiates resection at clean DNA double-strand breaks

Paudyal

Yan

et al. 2017

Nucleic Acids Research

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Nucleolytic resection of DNA double-strand breaks (DSBs) is essential for both checkpoint activation and homology-mediated repair; however, the precise mechanism of resection, especially the initiation step, remains incompletely understood. Resection of blocked ends with protein or chemical adducts is believed to be initiated by the MRN complex in conjunction with CtIP through internal cleavage of the 5′ strand DNA. However, it is not clear whether resection of clean DSBs with free ends is also initiated by the same mechanism. Using the Xenopus nuclear extract system, here we show that the Dna2 nuclease directly initiates the resection of clean DSBs by cleaving the 5′ strand DNA ∼10–20 nucleotides away from the ends. In the absence of Dna2, MRN together with CtIP mediate an alternative resection initiation pathway where the nuclease activity of MRN apparently directly cleaves the 5′ strand DNA at more distal sites. MRN also facilitates resection initiation by promoting the recruitment of Dna2 and CtIP to the DNA substrate. The ssDNA-binding protein RPA promotes both Dna2- and CtIP–MRN-dependent resection initiation, but a RPA mutant can distinguish between these pathways. Our results strongly suggest that resection of blocked and clean DSBs is initiated via distinct mechanisms.

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“…The MRN complex recognizes both exogeneous DSBs as well as damage that might arise in S-phase during DNA replication [ 3 , 41 , 42 ]. Homologous recombination requires long range resection to expose tracts of single stranded DNA which participate in homology search and strand invasion [ 43 ].…”

Section: Introductionmentioning

confidence: 99%

Mutation Spectra of the MRN (MRE11, RAD50, NBS1/NBN) Break Sensor in Cancer Cells

McPherson

Holub

Husbands

et al. 2020

Cancers

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The MRN complex (MRE11, RAD50, NBS1/NBN) is a DNA double strand break sensor in eukaryotes. The complex directly participates in, or coordinates, several activities at the break such as DNA resection, activation of the DNA damage checkpoint, chromatin remodeling and recruitment of the repair machinery. Mutations in components of the MRN complex have been described in cancer cells for several decades. Using the Catalogue of Somatic Mutations in Cancer (COSMIC) database, we characterized all the reported MRN mutations. This analysis revealed several hotspot frameshift mutations in all three genes that introduce premature stop codons and truncate large regions of the C-termini. We also found through evolutionary analyses that COSMIC mutations are enriched in conserved residues of NBS1/NBN and RAD50 but not in MRE11. Given that all three genes are important to carcinogenesis, we propose these differential enrichment patterns may reflect a more severe pleiotropic role for MRE11.

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Sharpening the ends for repair: mechanisms and regulation of DNA resection

Cited by 9 publications

References 231 publications

The MRN complex promotes DNA repair by homologous recombination and restrains antigenic variation in African trypanosomes

The MRN complex promotes DNA repair by homologous recombination and restrains antigenic variation in African trypanosomes

Dna2 initiates resection at clean DNA double-strand breaks

Mutation Spectra of the MRN (MRE11, RAD50, NBS1/NBN) Break Sensor in Cancer Cells

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