Ubiquitinated Fancd2 recruits Fan1 to stalled replication forks to prevent genome instability

Science
Christophe LachaudJohn Rouse

Abstract

Mono-ubiquitination of Fancd2 is essential for repairing DNA interstrand cross-links (ICLs), but the underlying mechanisms are unclear. The Fan1 nuclease, also required for ICL repair, is recruited to ICLs by ubiquitinated (Ub) Fancd2. This could in principle explain how Ub-Fancd2 promotes ICL repair, but we show that recruitment of Fan1 by Ub-Fancd2 is dispensable for ICL repair. Instead, Fan1 recruitment--and activity--restrains DNA replication fork progression and prevents chromosome abnormalities from occurring when DNA replication forks stall, even in the absence of ICLs. Accordingly, Fan1 nuclease-defective knockin mice are cancer-prone. Moreover, we show that a Fan1 variant in high-risk pancreatic cancers abolishes recruitment by Ub-Fancd2 and causes genetic instability without affecting ICL repair. Therefore, Fan1 recruitment enables processing of stalled forks that is essential for genome stability and health.

References

Mar 10, 2001·Molecular Cell·I Garcia-HigueraA D D'Andrea
Aug 2, 2003·Genes & Development·Scott HoughtalingMarkus Grompe
Jul 23, 2009·Mutation Research·Arleen D Auerbach
Jul 4, 2012·Genes & Development·Hyungjin Kim, Alan D D'Andrea
Oct 11, 2014·PloS One·Ivan M MunozChristophe Lachaud
Mar 4, 2015·The Journal of Cell Biology·Ralph ZellwegerMassimo Lopes
Jun 9, 2015·Molecular Cell·Andrew C KileKarlene A Cimprich

❮ Previous
Next ❯

Citations

Jun 24, 2016·Cilia·Colin A Johnson, Spencer J Collis
Apr 21, 2016·Cellular and Molecular Life Sciences : CMLS·David Lopez-MartinezMartin A Cohn
May 6, 2016·Nature Reviews. Molecular Cell Biology·Raphael CeccaldiAlan D D'Andrea
Jun 1, 2016·Frontiers in Genetics·Néstor García-RodríguezHelle D Ulrich
Jun 21, 2016·Nature Structural & Molecular Biology·Johanna MichlMadalena Tarsounas
Jul 6, 2016·Human Genomics·Daniel W NebertVasilis Vasiliou
Aug 4, 2016·Nature Structural & Molecular Biology·Christophe Lachaud, John Rouse
Aug 18, 2016·Endocrine-related Cancer·Amélie Fradet-TurcotteAlexandre Orthwein
Aug 24, 2016·Endocrine-related Cancer·Yoko Katsuki, Minoru Takata
Oct 22, 2016·Molecular Cell·Advaitha MadireddyCarl L Schildkraut
Mar 23, 2017·Nature Reviews. Molecular Cell Biology·Pierre-Marie Dehé, Pierre-Henri L Gaillard
Mar 21, 2017·Experimental Hematology·Winnie Tan, Andrew J Deans
Feb 28, 2017·Cell & Bioscience·Anna PalovcakYanbin Zhang
Jul 18, 2017·Nature Reviews. Genetics·Hervé TécherMichelle Debatisse
Aug 22, 2017·International Journal of Molecular Sciences·Manoj NepalPeiwen Fei
Oct 13, 2017·The Journal of Biological Chemistry·Yanyan TianLei Li
Feb 24, 2018·Cold Spring Harbor Symposia on Quantitative Biology·Sharon B Cantor, Jennifer A Calvo
Aug 29, 2018·The FEBS Journal·Wai Yan YauNicholas W Wood
Dec 19, 2018·Genes·Seong Min Kim, Susan L Forsburg
Oct 26, 2018·Human Molecular Genetics·Robert GooldSarah J Tabrizi
May 28, 2019·Genes & Development·Belén Gómez-González, Andrés Aguilera
Sep 10, 2019·Nucleic Acids Research·Huimin ZhangJunjie Chen
Feb 22, 2017·Cellular and Molecular Life Sciences : CMLS·Michele Giannattasio, Dana Branzei
Dec 14, 2016·The Journal of Cell Biology·Katherine S LawrenceJoAnne Engebrecht
Mar 9, 2018·The Journal of Biological Chemistry·Hyeonseok JinYunje Cho
Sep 28, 2018·International Journal of Molecular Sciences·Maïlyn Yates, Alexandre Maréchal
Jan 20, 2020·Genes to Cells : Devoted to Molecular & Cellular Mechanisms·Mihoko RikitakeMasumi Hidaka
Jul 22, 2019·DNA Repair·Julie RageulHyungjin Kim
Jul 13, 2020·Seminars in Cell & Developmental Biology·Stephanie TyeJoanna R Morris
Dec 31, 2020·Proceedings of the National Academy of Sciences of the United States of America·Rui WangLei Li
Feb 14, 2021·Journal of Huntington's Disease·Amit L DeshmukhChristopher E Pearson

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.