A Biochemically Defined System for Coding Joint Formation in V(D)J Recombination

Lu, Haihui; Shimazaki, Noriko; Raval, Prafulla; Gu, Jiafeng; Watanabe, Go; Schwarz, Klaus; Swanson, Patrick C.; Lieber, Michael R.

doi:10.1016/j.molcel.2008.05.029

Cited by 37 publications

(45 citation statements)

References 74 publications

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“…Some minor bands below the top band (bracket) were by-products of the model system, because these shorter products cannot be observed when the same translocation-specific PCR was performed to detect de novo translocations in sperm samples from human males. ARTICLE activation of the Artemis:DNA-PKcs complex to produce a nick at the hairpin tip 54 . A final step is NHEJ that leads to illegitimate chromosomal rejoining by ligase IV.…”

Section: Discussionmentioning

confidence: 99%

Two sequential cleavage reactions on cruciform DNA structures cause palindrome-mediated chromosomal translocations

et al. 2013

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Gross chromosomal rearrangements (GCRs), such as translocations, deletions or inversions, are often generated by illegitimate repair between two DNA breakages at regions with nucleotide sequences that might potentially adopt a non-B DNA conformation. We previously established a plasmid-based model system that recapitulates palindrome-mediated recurrent chromosomal translocations in humans, and demonstrated that cruciform DNA conformation is required for the translocation-like rearrangements. Here we show that two sequential reactions that cleave the cruciform structures give rise to the translocation: GEN1-mediated resolution that cleaves diagonally at the four-way junction of the cruciform and Artemismediated opening of the subsequently formed hairpin ends. Indeed, translocation products in human sperm reveal the remnants of this two-step mechanism. These two intrinsic pathways that normally fulfil vital functions independently, Holliday-junction resolution in homologous recombination and coding joint formation in rearrangement of antigen-receptor genes, act upon the unusual DNA conformation in concert and lead to a subset of recurrent GCRs in humans.

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Section: Discussionmentioning

confidence: 99%

Two sequential cleavage reactions on cruciform DNA structures cause palindrome-mediated chromosomal translocations

et al. 2013

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“…The endonuclease activity of the Artemis·DNA-PKcs complex can remove both 5' and 3' DNA overhangs in order to create DNA end structures that can be ligated by the XRCC4·Lig4 complex (50,86) (Fig. 3).…”

Section: The Nucleases Of Nhej Can Process Multiple Dna End Configuramentioning

confidence: 99%

Nonhomologous DNA end-joining for repair of DNA double-strand breaks

Pannunzio

Watanabe

Lieber

2018

Journal of Biological Chemistry

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387

360

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Nonhomologous DNA end joining (NHEJ) is the predominant DSB repair pathway throughout the cell cycle and accounts for nearly all DSB repair outside of the S and G2 phases. NHEJ relies on Ku to thread onto DNA termini and thereby improve the affinity of the NHEJ enzymatic components consisting of polymerases (Pol m and Pol l), a nuclease (the Artemis·DNA-PKcs complex), and a ligase (XLF·XRCC4·Lig4 complex). Each of the enzymatic components is distinctive for its versatility in acting on diverse incompatible DNA end configurations coupled with a flexibility in loading order, resulting in many possible junctional outcomes from one DSB. DNA ends can either be directly ligated or, if the ends are incompatible, processed until a ligatable configuration is achieved that is often stabilized by up to 4 bp of terminal microhomology. Processing of DNA ends results in nucleotide loss or addition, explaining why DSBs repaired by NHEJ are rarely restored to their original DNA sequence. Thus, NHEJ is a single pathway with multiple enzymes at its disposal to repair DSBs, resulting in a diversity of repair outcomes.

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“…We have determined biochemically that Artemis, in complex with DNA-PKcs, resects 5Ј and 3Ј DNA overhangs to create DNA end structures that are able to be ligated by the DNA ligase IV-XRCC4 complex (11,12). At 5Ј overhangs, Artemis cuts directly at the ss/dsDNA boundary.…”

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confidence: 99%