UHRF1 Is a Sensor for DNA Interstrand Crosslinks and Recruits FANCD2 to Initiate the Fanconi Anemia Pathway
Copyright policy )UHRF1 Is a Sensor for DNA Interstrand Crosslinks and Recruits FANCD2 to Initiate the Fanconi Anemia Pathway
The Fanconi anemia (FA) pathway is critical for the cellular response to toxic DNA interstrand crosslinks (ICLs). Using a biochemical purification strategy, we identified UHRF1 as a protein that specifically interacts with ICLs in vitro and in vivo. Reduction of cellular levels of UHRF1 by RNAi attenuates the FA pathway and sensitizes cells to mitomycin C. Knockdown cells display a drastic reduction in FANCD2 foci formation. Using live-cell imaging, we observe that UHRF1 is rapidly recruited to chromatin in response to DNA crosslinking agents and that this recruitment both precedes and is required for the recruitment of FANCD2 to ICLs. Based on these results, we describe a mechanism of ICL sensing and propose that UHRF1 is a critical factor that binds to ICLs. In turn, this binding is necessary for the subsequent recruitment of FANCD2, which allows the DNA repair process to initiate.
- University of Oxford United Kingdom
- Department of Cell Biology Harvard Medical School United States
- University of Oxford / Biochemistry Department United Kingdom
- Wellcome Trust United Kingdom
- Umeå University Sweden
Medicin och hälsovetenskap, DNA Repair, QH301-705.5, Fanconi Anemia Complementation Group D2 Protein, Ubiquitin-Protein Ligases, DNA, Biological Sciences, Medical and Health Sciences, Chromatin, Fanconi Anemia, Report, CCAAT-Enhancer-Binding Proteins, Humans, Biologiska vetenskaper, Amino Acid Sequence, Biology (General), DNA Damage
Medicin och hälsovetenskap, DNA Repair, QH301-705.5, Fanconi Anemia Complementation Group D2 Protein, Ubiquitin-Protein Ligases, DNA, Biological Sciences, Medical and Health Sciences, Chromatin, Fanconi Anemia, Report, CCAAT-Enhancer-Binding Proteins, Humans, Biologiska vetenskaper, Amino Acid Sequence, Biology (General), DNA Damage
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).78 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 1%
Citations provided by BIP!Popularity provided by BIP!