53BP1 cooperation with the REV7–shieldin complex underpins DNA structure-specific NHEJ

Hind Ghezraoui, Catarina Oliveira, Jordan R. Becker, Kirstin Bilham, Daniela Moralli, Consuelo Anzilotti, Roman Fischer, Mukta Deobagkar-Lele, Maria Sanchiz-Calvo, Elena Fueyo-Marcos, Sarah Bonham, Benedikt M. Kessler, Sven Rottenberg, Richard J. Cornall, Catherine M. Green and J. Ross Chapman ()
Additional contact information
Hind Ghezraoui: Wellcome Centre for Human Genetics, University of Oxford
Catarina Oliveira: Wellcome Centre for Human Genetics, University of Oxford
Jordan R. Becker: Wellcome Centre for Human Genetics, University of Oxford
Kirstin Bilham: Wellcome Centre for Human Genetics, University of Oxford
Daniela Moralli: Wellcome Centre for Human Genetics, University of Oxford
Consuelo Anzilotti: University of Oxford
Roman Fischer: University of Oxford
Mukta Deobagkar-Lele: University of Oxford
Maria Sanchiz-Calvo: Wellcome Centre for Human Genetics, University of Oxford
Elena Fueyo-Marcos: Wellcome Centre for Human Genetics, University of Oxford
Sarah Bonham: University of Oxford
Benedikt M. Kessler: University of Oxford
Sven Rottenberg: Vetsuisse Faculty, University of Bern
Richard J. Cornall: University of Oxford
Catherine M. Green: Wellcome Centre for Human Genetics, University of Oxford
J. Ross Chapman: Wellcome Centre for Human Genetics, University of Oxford

Nature, 2018, vol. 560, issue 7716, 122-127

Abstract: Abstract 53BP1 governs a specialized, context-specific branch of the classical non-homologous end joining DNA double-strand break repair pathway. Mice lacking 53bp1 (also known as Trp53bp1) are immunodeficient owing to a complete loss of immunoglobulin class-switch recombination1,2, and reduced fidelity of long-range V(D)J recombination3. The 53BP1-dependent pathway is also responsible for pathological joining events at dysfunctional telomeres4, and its unrestricted activity in Brca1-deficient cellular and tumour models causes genomic instability and oncogenesis5–7. Cells that lack core non-homologous end joining proteins are profoundly radiosensitive8, unlike 53BP1-deficient cells9,10, which suggests that 53BP1 and its co-factors act on specific DNA substrates. Here we show that 53BP1 cooperates with its downstream effector protein REV7 to promote non-homologous end joining during class-switch recombination, but REV7 is not required for 53BP1-dependent V(D)J recombination. We identify shieldin—a four-subunit putative single-stranded DNA-binding complex comprising REV7, c20orf196 (SHLD1), FAM35A (SHLD2) and FLJ26957 (SHLD3)—as the factor that explains this specificity. Shieldin is essential for REV7-dependent DNA end-protection and non-homologous end joining during class-switch recombination, and supports toxic non-homologous end joining in Brca1-deficient cells, yet is dispensable for REV7-dependent interstrand cross-link repair. The 53BP1 pathway therefore comprises distinct double-strand break repair activities within chromatin and single-stranded DNA compartments, which explains both the immunological differences between 53bp1- and Rev7- deficient mice and the context specificity of the pathway.

Date: 2018
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DOI: 10.1038/s41586-018-0362-1

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