1. ATR Promotes the Replication Traverse of DNA Interstrand Crosslinks
- Author
-
Yutong Xue, Jing Huang, Marina A. Bellani, Weidong Wang, Michael A. Seidman, and Amom Ruhikanta Meetei
- Subjects
Genome instability ,Premature aging ,congenital, hereditary, and neonatal diseases and abnormalities ,biology ,DNA synthesis ,Chemistry ,nutritional and metabolic diseases ,Helicase ,medicine.disease ,Biochemistry ,Cell biology ,chemistry.chemical_compound ,Fanconi anemia ,hemic and lymphatic diseases ,FANCD2 ,Genetics ,biology.protein ,medicine ,FANCM ,Molecular Biology ,DNA ,Biotechnology - Abstract
DNA instability disorders are associated with cancer, neurodegeneration, and premature aging. The genome integrity is most vulnerable during S phase during which the replication apparatus encounters many impediments. Among the most severe are interstrand crosslinks (ICLs) which are absolute blocks to helicases, and have always been regarded as absolute blocks to replication. Cells from patients with the genome instability disorder Fanconi Anemia (FA) are highly sensitive to crosslinking agents. We have developed a novel single molecule strategy, based on DNA fibers, to visualize collisions of replication forks with ICLs. Remarkably, we found that DNA synthesis can resume past an ICL, leaving behind still crosslinked parental strands, a process that requires only a few minutes. Traverse of ICLs requires the activity of the Fanconi Anemia translocase FANCM. Furthermore, while the FA “core” complex proteins, which monoubiquitinate the FANCD2 protein, were not required, FANCD2 was. These results indicate that...
- Published
- 2015
- Full Text
- View/download PDF