FANCD2 Facilitates Replication through Common Fragile Sites

Advaitha Madireddy, Settapong T. Kosiyatrakul, Rebecca A. Boisvert, Emilia Herrera-Moyano, María L. García-Rubio, Jeannine Gerhardt, Elizabeth A. Vuono, Nichole Owen, Zi Yan, Susan Olson, Andrés Aguilera, Niall G. Howlett, Carl L. Schildkraut

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)388-404
Number of pages17
JournalMolecular Cell
Volume64
Issue number2
DOIs
StatePublished - Oct 20 2016

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Fanconi Anemia Complementation Group D2 Protein
RNA
DNA

Keywords

  • cancer
  • common fragile sites
  • DNA replication
  • DNA:RNA hybrids
  • Fanconi anemia
  • genomic instability

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Madireddy, A., Kosiyatrakul, S. T., Boisvert, R. A., Herrera-Moyano, E., García-Rubio, M. L., Gerhardt, J., ... Schildkraut, C. L. (2016). FANCD2 Facilitates Replication through Common Fragile Sites. Molecular Cell, 64(2), 388-404. https://doi.org/10.1016/j.molcel.2016.09.017

FANCD2 Facilitates Replication through Common Fragile Sites. / Madireddy, Advaitha; Kosiyatrakul, Settapong T.; Boisvert, Rebecca A.; Herrera-Moyano, Emilia; García-Rubio, María L.; Gerhardt, Jeannine; Vuono, Elizabeth A.; Owen, Nichole; Yan, Zi; Olson, Susan; Aguilera, Andrés; Howlett, Niall G.; Schildkraut, Carl L.

In: Molecular Cell, Vol. 64, No. 2, 20.10.2016, p. 388-404.

Research output: Contribution to journalArticle

Madireddy, A, Kosiyatrakul, ST, Boisvert, RA, Herrera-Moyano, E, García-Rubio, ML, Gerhardt, J, Vuono, EA, Owen, N, Yan, Z, Olson, S, Aguilera, A, Howlett, NG & Schildkraut, CL 2016, 'FANCD2 Facilitates Replication through Common Fragile Sites', Molecular Cell, vol. 64, no. 2, pp. 388-404. https://doi.org/10.1016/j.molcel.2016.09.017
Madireddy A, Kosiyatrakul ST, Boisvert RA, Herrera-Moyano E, García-Rubio ML, Gerhardt J et al. FANCD2 Facilitates Replication through Common Fragile Sites. Molecular Cell. 2016 Oct 20;64(2):388-404. https://doi.org/10.1016/j.molcel.2016.09.017
Madireddy, Advaitha ; Kosiyatrakul, Settapong T. ; Boisvert, Rebecca A. ; Herrera-Moyano, Emilia ; García-Rubio, María L. ; Gerhardt, Jeannine ; Vuono, Elizabeth A. ; Owen, Nichole ; Yan, Zi ; Olson, Susan ; Aguilera, Andrés ; Howlett, Niall G. ; Schildkraut, Carl L. / FANCD2 Facilitates Replication through Common Fragile Sites. In: Molecular Cell. 2016 ; Vol. 64, No. 2. pp. 388-404.
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