53BP1-RIF1-shieldin counteracts DSB resection through CST- and Polα-dependent fill-in

Nature
Zachary MirmanTitia de Lange

Abstract

In DNA repair, the resection of double-strand breaks dictates the choice between homology-directed repair-which requires a 3' overhang-and classical non-homologous end joining, which can join unresected ends1,2. BRCA1-mutant cancers show minimal resection of double-strand breaks, which renders them deficient in homology-directed repair and sensitive to inhibitors of poly(ADP-ribose) polymerase 1 (PARP1)3-8. When BRCA1 is absent, the resection of double-strand breaks is thought to be prevented by 53BP1, RIF1 and the REV7-SHLD1-SHLD2-SHLD3 (shieldin) complex, and loss of these factors diminishes sensitivity to PARP1 inhibitors4,6-9. Here we address the mechanism by which 53BP1-RIF1-shieldin regulates the generation of recombinogenic 3' overhangs. We report that CTC1-STN1-TEN1 (CST)10, a complex similar to replication protein A that functions as an accessory factor of polymerase-α (Polα)-primase11, is a downstream effector in the 53BP1 pathway. CST interacts with shieldin and localizes with Polα to sites of DNA damage in a 53BP1- and shieldin-dependent manner. As with loss of 53BP1, RIF1 or shieldin, the depletion of CST leads to increased resection. In BRCA1-deficient cells, CST blocks RAD51 loading and promotes the efficacy of P...Continue Reading

References

Feb 26, 1998·Cell·B van SteenselT de Lange
Feb 26, 1999·Science·J KarlsederT de Lange
May 25, 1999·Cell·J D GriffithT de Lange
Dec 13, 2000·Molecular and Cellular Biology·O K Mirzoeva, J H Petrini
Jun 22, 2005·Nature Cell Biology·Giulia B Celli, Titia de Lange
Dec 28, 2007·Cell·Hiroyuki TakaiTitia de Lange
Aug 6, 2008·Annual Review of Genetics·Wilhelm Palm, Titia de Lange
Dec 10, 2009·Molecular and Cellular Biology·Tatsuya KibeTitia de Lange
May 11, 2010·Nature Structural & Molecular Biology·Peter BouwmanJos Jonkers
Aug 11, 2010·Cell Cycle·Carolyn M PriceDorothy E Shippen
May 5, 2012·Science·Agnel Sfeir, Titia de Lange
Jan 12, 2013·Science·Michal ZimmermannTitia de Lange
Jan 25, 2013·Proceedings of the National Academy of Sciences of the United States of America·Francisca LottersbergerTitia de Lange
Feb 5, 2013·Nature Structural & Molecular Biology·Jiangbo TangRoger A Greenberg
Oct 8, 2013·Trends in Cell Biology·Michal Zimmermann, Titia de Lange
Dec 12, 2013·Nature Reviews. Molecular Cell Biology·Stephanie Panier, Simon J Boulton
Nov 7, 2015·Cell·Francisca LottersbergerTitia de Lange
Jan 19, 2016·Molecular Cell·Tatsuya KibeTitia de Lange
May 12, 2016·Nature Reviews. Molecular Cell Biology·Eros Lazzerini-Denchi, Agnel Sfeir
Jun 28, 2016·Nature Structural & Molecular Biology·Fena OchsClaudia Lukas
Jan 25, 2017·Genes & Development·Yi GongTitia de Lange
Mar 24, 2017·Nucleic Acids Research·Xuyang FengCarolyn M Price
Jul 21, 2017·Biochemistry·Robert A Hom, Deborah S Wuttke
Jul 20, 2018·Nature·Sylvie M NoordermeerDaniel Durocher

❮ Previous
Next ❯

Citations

Sep 13, 2018·Annual Review of Genetics·Titia de Lange
Dec 16, 2018·Genes·Meghan R Sullivan, Kara A Bernstein
Mar 27, 2019·Cancers·Ainhoa MadariagaAmit M Oza
Apr 16, 2019·Nucleic Acids Research·Kirk L WestJustin W C Leung
Apr 23, 2019·Nucleic Acids Research·Olga CalvoMichel Charbonneau
Apr 13, 2019·Nucleic Acids Research·Miaomiao ZhangFeng Wang
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
Dec 4, 2019·Nature Structural & Molecular Biology·Indrajeet Ghodke, Evi Soutoglou
Jan 4, 2020·Genes & Development·Zachary Mirman, Titia de Lange
Mar 4, 2020·Cancers·Nalini SrinivasRajiv Kumar
Feb 26, 2020·EMBO Reports·Liudmyla LototskaAaron Mendez-Bermudez
Nov 16, 2019·Cellular and Molecular Life Sciences : CMLS·Eric M SmithJayakrishnan Nandakumar
May 28, 2019·Current Genetics·Aurèle Piazza, Wolf-Dietrich Heyer
May 19, 2020·Cell Cycle·Prabha SarangiAlan D D'Andrea
Apr 20, 2020·Environmental and Molecular Mutagenesis·Kylie FackrellJunya Tomida
Jul 11, 2020·Essays in Biochemistry·Yixi Xu, Dongyi Xu
Jul 28, 2018·Nature Cell Biology·Roger A Greenberg
Feb 20, 2020·Cell & Bioscience·Jia YuZhenkun Lou
Jun 23, 2020·Nucleus·Leonid A Timashev, Titia De Lange
Jun 6, 2020·Nature Communications·Dingpeng YangFei-Long Meng
Sep 28, 2018·International Journal of Molecular Sciences·Maïlyn Yates, Alexandre Maréchal
Jul 20, 2018·Nature·Sylvie M NoordermeerDaniel Durocher
Jan 24, 2019·The Journal of Cell Biology·Kimberly Rickman, Agata Smogorzewska
Nov 23, 2018·Nature·Yizhou Joseph HeDipanjan Chowdhury
Dec 30, 2018·Genome Medicine·Paola Francica, Sven Rottenberg
Apr 14, 2019·Life Science Alliance·Yilin WangJason A Stewart
Jun 12, 2019·Nature Communications·Gabriele A FontanaUlrich Rass
Jan 10, 2020·Nature Cell Biology·Connor S ClairmontAlan D D'Andrea
Sep 5, 2020·NAR Cancer·Taejoo HwangKei-Ichi Takata
Jul 6, 2019·Nature Communications·Marie-Christine CaronJean-Yves Masson
Sep 27, 2019·Frontiers in Molecular Biosciences·Susanne C S Bantele, Boris Pfander
Feb 26, 2020·Nature Reviews. Molecular Cell Biology·Madalena Tarsounas, Patrick Sung
Aug 7, 2020·Essays in Biochemistry·Ajinkya S Kawale, Patrick Sung

❮ Previous
Next ❯

Methods Mentioned

BETA
two-hybrid
PCR
FACS
scraping

Software Mentioned

Transnetyx
Volocity
ImageQuant
FIJI
SoftWoRx
Epistasis

Related Concepts

Related Feeds

Breast Cancer: BRCA1 & BRCA2

Mutations involving BRCA1, found on chromosome 17, and BRCA2, found on chromosome 13, increase the risk for specific cancers, such as breast cancer. Discover the last research on breast cancer BRCA1 and BRCA2 here.