FANCD2 Facilitates Replication through Common Fragile Sites.

TitleFANCD2 Facilitates Replication through Common Fragile Sites.
Publication TypeJournal Article
Year of Publication2016
AuthorsMadireddy A, Kosiyatrakul ST, Boisvert RA, Herrera-Moyano E, GarcĂ­a-Rubio ML, Gerhardt J, Vuono EA, Owen N, Yan Z, Olson S, Aguilera A, Howlett NG, Schildkraut CL
JournalMol Cell
Date Published2016 10 20
KeywordsBRCA2 Protein, Cell Line, Transformed, Chromosome Fragile Sites, DNA, DNA Replication, Fanconi Anemia, Fanconi Anemia Complementation Group A Protein, Fanconi Anemia Complementation Group D2 Protein, Fanconi Anemia Complementation Group Proteins, Fibroblasts, Gene Expression, Genomic Instability, Herpesvirus 4, Human, Humans, Lymphocytes, RNA

Common fragile sites (CFSs) are genomic regions that are unstable under conditions of replicative stress. Although the characteristics of CFSs that render them vulnerable to stress are associated mainly with replication, the cellular pathways that protect CFSs during replication remain unclear. Here, we identify and describe a role for FANCD2 as a trans-acting facilitator of CFS replication, in the absence of exogenous replicative stress. In the absence of FANCD2, replication forks stall within the AT-rich fragility core of CFS, leading to dormant origin activation. Furthermore, FANCD2 deficiency is associated with DNA:RNA hybrid formation at CFS-FRA16D, and inhibition of DNA:RNA hybrid formation suppresses replication perturbation. In addition, we also found that FANCD2 reduces the number of potential sites of replication initiation. Our data demonstrate that FANCD2 protein is required to ensure efficient CFS replication and provide mechanistic insight into how FANCD2 regulates CFS stability.

Alternate JournalMol. Cell
PubMed ID27768874
PubMed Central IDPMC5683400
Grant ListP20 GM103430 / GM / NIGMS NIH HHS / United States
R01 GM045751 / GM / NIGMS NIH HHS / United States
R01 HL101977 / HL / NHLBI NIH HHS / United States