Shieldin complex promotes DNA end-joining and counters homologous recombination in BRCA1-null cells.

Nature Cell Biology
Harveer DevStephen P Jackson

Abstract

BRCA1 deficiencies cause breast, ovarian, prostate and other cancers, and render tumours hypersensitive to poly(ADP-ribose) polymerase (PARP) inhibitors. To understand the resistance mechanisms, we conducted whole-genome CRISPR-Cas9 synthetic-viability/resistance screens in BRCA1-deficient breast cancer cells treated with PARP inhibitors. We identified two previously uncharacterized proteins, C20orf196 and FAM35A, whose inactivation confers strong PARP-inhibitor resistance. Mechanistically, we show that C20orf196 and FAM35A form a complex, 'Shieldin' (SHLD1/2), with FAM35A interacting with single-stranded DNA through its C-terminal oligonucleotide/oligosaccharide-binding fold region. We establish that Shieldin acts as the downstream effector of 53BP1/RIF1/MAD2L2 to promote DNA double-strand break (DSB) end-joining by restricting DSB resection and to counteract homologous recombination by antagonizing BRCA2/RAD51 loading in BRCA1-deficient cells. Notably, Shieldin inactivation further sensitizes BRCA1-deficient cells to cisplatin, suggesting how defining the SHLD1/2 status of BRCA1-deficient tumours might aid patient stratification and yield new treatment opportunities. Highlighting this potential, we document reduced SHLD1/2 ex...Continue Reading

References

Feb 1, 1996·International Immunology·M NakamuraT Honjo
May 26, 2004·The Journal of Cell Biology·Irene M WardJunjie Chen
Aug 28, 2007·Nature Methods·Jesper V OlsenMatthias Mann
Oct 23, 2009·Nature·Stephen P Jackson, Jiri Bartek
Dec 17, 2009·Genes & Development·Jia SunMing Lei
Sep 14, 2010·Molecular Cell·Marie-Josèphe Giraud-PanisEric Gilson
Nov 3, 2010·DNA Repair·Simon Bekker-Jensen, Niels Mailand
Jan 6, 2011·Proceedings of the National Academy of Sciences of the United States of America·Kosuke YusaNancy L Craig
Jan 25, 2011·Journal of Proteome Research·Jürgen CoxMatthias Mann
Jun 7, 2011·Molecular & Cellular Proteomics : MCP·Annette MichalskiStevan Horning
Jul 12, 2011·Nature Methods·Michael T CertoAndrew M Scharenberg
Aug 23, 2011·Nature Cell Biology·Marieke H Peuscher, Jacqueline J L Jacobs
Mar 27, 2012·Molecular Cell·Samuel F BuntingAndré Nussenzweig
Jun 5, 2012·Genes & Development·Yaron GalantyStephen P Jackson
Jan 12, 2013·Science·Michal ZimmermannTitia de Lange
Jan 12, 2013·Science·Michela Di VirgilioMichel C Nussenzweig
Mar 12, 2013·Molecular Cell·James M Daley, Patrick Sung
Aug 7, 2013·Mutation Research·Ralph Scully, Anyong Xie
Nov 10, 2013·Nature Medicine·Christopher J Lord, Alan Ashworth
Dec 18, 2013·Science·Ophir ShalemFeng Zhang
Dec 24, 2013·The British Journal of Radiology·A Kakarougkas, P A Jeggo
Oct 15, 2014·Cell Reports·Andrés Cruz-GarcíaPablo Huertas
Nov 26, 2014·Annual Review of Medicine·Michael Goldstein, Michael B Kastan
Mar 5, 2015·DNA Repair·Alena V Makarova, Peter M Burgers
Oct 27, 2015·Nature Cell Biology·Christine K SchmidtStephen P Jackson
Feb 3, 2016·Nature Communications·Chloé LescaleLudovic Deriano

❮ Previous
Next ❯

Citations

Sep 14, 2018·Bioscience Reports·Andrew CubbonEdward L Bolt
Feb 28, 2019·Nucleic Acids Research·Naike Salvador MorenoPierre-Alexandre Vidi
Apr 16, 2019·Nucleic Acids Research·Kirk L WestJustin W C Leung
May 23, 2019·Cell Cycle·Ron D JachimowiczH Christian Reinhardt
Jul 4, 2019·The EMBO Journal·Sinan KilicMatthias Altmeyer
Apr 6, 2019·EMBO Reports·Dheva Setiaputra, Daniel Durocher
Aug 30, 2018·The EMBO Journal·Steven FindlayAlexandre Orthwein
Jul 3, 2019·Nature Reviews. Molecular Cell Biology·Ralph ScullyNicholas A Willis
Aug 24, 2019·Genome Medicine·Medina ColicTraver Hart
Sep 26, 2019·Frontiers in Molecular Biosciences·Ruth M Densham, Joanna R Morris
Jun 21, 2019·Annals of Oncology : Official Journal of the European Society for Medical Oncology·J MateoJ S de Bono
Oct 16, 2019·The EMBO Journal·Abhay Narayan SinghKristijan Ramadan
Dec 4, 2019·Nature Structural & Molecular Biology·Indrajeet Ghodke, Evi Soutoglou
Jan 4, 2020·Genes & Development·Zachary Mirman, Titia de Lange
Feb 23, 2020·International Journal of Molecular Sciences·Giovanni PasquiniVolker Busskamp
Feb 8, 2020·Genes & Development·Dea Slade
Dec 10, 2019·Current Opinion in Obstetrics & Gynecology·Kari Kubalanza, Gottfried E Konecny
May 19, 2020·Cell Cycle·Prabha SarangiAlan D D'Andrea
Jul 2, 2020·International Journal of Molecular Sciences·Stefania CoccoMichelino De Laurentiis
Apr 20, 2020·Environmental and Molecular Mutagenesis·Kylie FackrellJunya Tomida
Jul 11, 2020·Essays in Biochemistry·Yixi Xu, Dongyi Xu
Sep 27, 2018·Nature Communications·Shengxian GaoDongyi Xu
Sep 28, 2018·International Journal of Molecular Sciences·Maïlyn Yates, Alexandre Maréchal
Jun 12, 2019·Nature Communications·Gabriele A FontanaUlrich Rass
Mar 26, 2020·Cell Biology International·Caglar Berkel, Ercan Cacan
Feb 26, 2020·Nature Reviews. Molecular Cell Biology·Madalena Tarsounas, Patrick Sung
May 21, 2020·Frontiers in Oncology·Martin LiptaySven Rottenberg
Aug 14, 2020·Cells·Radoslav AleksandrovAnastas Gospodinov
Jul 28, 2018·Nature Cell Biology·Roger A Greenberg
Dec 30, 2018·Genome Medicine·Paola Francica, Sven Rottenberg
Sep 27, 2019·Frontiers in Molecular Biosciences·Susanne C S Bantele, Boris Pfander
Apr 30, 2020·Nucleic Acids Research·Sean Michael HowardPetr Cejka
Jun 6, 2020·Nature Communications·Dingpeng YangFei-Long Meng
Aug 12, 2020·Journal of Radiation Research·Atsushi Shibata, Penny A Jeggo
Aug 7, 2020·Essays in Biochemistry·Ajinkya S Kawale, Patrick Sung
Oct 19, 2019·Targeted Oncology·Esha SachdevMonica M Mita
Jan 24, 2019·The Journal of Cell Biology·Kimberly Rickman, Agata Smogorzewska
Jan 10, 2020·Nature Cell Biology·Connor S ClairmontAlan D D'Andrea
Aug 10, 2019·Proceedings of the National Academy of Sciences of the United States of America·Gayathri SrinivasanRobert Hromas
Aug 1, 2019·Nature Communications·Tarun S NambiarAlberto Ciccia
Sep 25, 2020·Proceedings of the National Academy of Sciences of the United States of America·Sophie LoeilletAlain G Nicolas

❮ Previous
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Datasets Mentioned

BETA
PXD009830

Methods Mentioned

BETA
sumoylation
xenograft
co-immunoprecipitation
super-resolution microscopy
chromosomal aberrations
biopsies
PCR
Illumina sequencing
transfection
transfections

Software Mentioned

STAR
MaxQuant
MAGeCK
SoftWoRx
Affymetrix
Trim Galore
ImageJ
FIJI
GraphPad
Volocity

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