Chromosomal Integrity after UV Irradiation Requires FANCD2-Mediated Repair of Double Strand Breaks

PLoS Genetics
María Belén FedericoVanesa Gottifredi

Abstract

Fanconi Anemia (FA) is a rare autosomal recessive disorder characterized by hypersensitivity to inter-strand crosslinks (ICLs). FANCD2, a central factor of the FA pathway, is essential for the repair of double strand breaks (DSBs) generated during fork collapse at ICLs. While lesions different from ICLs can also trigger fork collapse, the contribution of FANCD2 to the resolution of replication-coupled DSBs generated independently from ICLs is unknown. Intriguingly, FANCD2 is readily activated after UV irradiation, a DNA-damaging agent that generates predominantly intra-strand crosslinks but not ICLs. Hence, UV irradiation is an ideal tool to explore the contribution of FANCD2 to the DNA damage response triggered by DNA lesions other than ICL repair. Here we show that, in contrast to ICL-causing agents, UV radiation compromises cell survival independently from FANCD2. In agreement, FANCD2 depletion does not increase the amount of DSBs generated during the replication of UV-damaged DNA and is dispensable for UV-induced checkpoint activation. Remarkably however, FANCD2 protects UV-dependent, replication-coupled DSBs from aberrant processing by non-homologous end joining, preventing the accumulation of micronuclei and chromatid abe...Continue Reading

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Citations

Jan 23, 2017·Free Radical Biology & Medicine·André Passaglia SchuchCamila Carrião Machado Garcia
Nov 14, 2019·PloS One·Gayle P PouliotAlejandro Gutierrez
Jul 29, 2018·Nature Genetics·Chris D RichardsonJacob E Corn
Jun 23, 2019·International Journal of Cancer. Journal International Du Cancer·Xiang ZengMasaki Mandai
Mar 21, 2019·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Sofía CarbajosaGastón Soria
Aug 20, 2021·Environmental Science and Pollution Research International·Keshav GoyalSandeep Mittan

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Datasets Mentioned

BETA
GM00637

Methods Mentioned

BETA
Flow cytometry
ubiquitination
chromosomal aberrations
Electrophoresis
transfection
Assay
fluorescence activated cell sorting
Chromosomal aberration
PCR

Software Mentioned

Excel
DAKO Cytomation
Dharmacon
Summit
GraphPad Prism
Invitrogen Block - iT RNAi Designer
ImageJ
Image Quant LAS4000

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