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Fanconi anemia and the cell cycle: new perspectives on aneuploidy.

Nalepa G, Clapp DW - F1000Prime Rep (2014)

Bottom Line: Loss of FA signaling causes chromosome instability by weakening the spindle assembly checkpoint, disrupting centrosome maintenance, disturbing resolution of ultrafine anaphase bridges, and dysregulating cytokinesis.Thus, the FA genes function as guardians of genome stability throughout the cell cycle.These new discoveries may facilitate the development of rational therapeutic strategies for FA and for FA-deficient malignancies in the general population.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Indiana University School of Medicine, Riley Hospital for Children 705 Riley Hospital Drive, Indianapolis, IN 46202 USA ; Division of Pediatric Hematology-Oncology, Indiana University School of Medicine, Riley Hospital for Children 705 Riley Hospital Drive, Indianapolis, IN 46202 USA ; Department of Medical and Molecular Genetics, Wells Center for Pediatric Research 1044 W. Walnut Street, Indiana University School of Medicine, Indianapolis, IN 46202 USA.

ABSTRACT
Fanconi anemia (FA) is a complex heterogenic disorder of genomic instability, bone marrow failure, cancer predisposition, and congenital malformations. The FA signaling network orchestrates the DNA damage recognition and repair in interphase as well as proper execution of mitosis. Loss of FA signaling causes chromosome instability by weakening the spindle assembly checkpoint, disrupting centrosome maintenance, disturbing resolution of ultrafine anaphase bridges, and dysregulating cytokinesis. Thus, the FA genes function as guardians of genome stability throughout the cell cycle. This review discusses recent advances in diagnosis and clinical management of Fanconi anemia and presents the new insights into the origins of genomic instability in FA. These new discoveries may facilitate the development of rational therapeutic strategies for FA and for FA-deficient malignancies in the general population.

No MeSH data available.


Related in: MedlinePlus

Fanconi anemia (FA) signaling is essential for DNA damage repair in interphaseDNA damage in interphase due to genotoxic stress stimulates the DNA damage kinase network, which triggers assembly of the FA core complex followed by monoubiquitination of the FANCD2/FANCI heterodimer and activation of DNA damage repair processes. Abbreviations: Ub, ubiquitination.
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fig-001: Fanconi anemia (FA) signaling is essential for DNA damage repair in interphaseDNA damage in interphase due to genotoxic stress stimulates the DNA damage kinase network, which triggers assembly of the FA core complex followed by monoubiquitination of the FANCD2/FANCI heterodimer and activation of DNA damage repair processes. Abbreviations: Ub, ubiquitination.

Mentions: All known FA proteins work in concert to control the DNA damage response (Fig. 1). Disrupted chromatin activates a network of kinases (including ATR and CHK1) to engage DNA damage pathways and arrest the cell cycle until the lesions are removed from the genome [43]. Some FA proteins are essential for this initial step in damage signal transduction: FANCM activates ATR [44] and CHK1 [45], and FANCJ promotes ATR-mediated cell cycle checkpoint signaling [46]. In return, ATR and CHK1 phosphorylate FANCA, FANCE, and FANCM [47-50]. This positive feedback loop connects the DNA damage kinases and FA proteins to amplify the DNA damage recognition signal. This in turn promotes the activation and assembly of the multiprotein FA core complex, which consists of eight FA proteins as well as several accessory proteins [51,52].


Fanconi anemia and the cell cycle: new perspectives on aneuploidy.

Nalepa G, Clapp DW - F1000Prime Rep (2014)

Fanconi anemia (FA) signaling is essential for DNA damage repair in interphaseDNA damage in interphase due to genotoxic stress stimulates the DNA damage kinase network, which triggers assembly of the FA core complex followed by monoubiquitination of the FANCD2/FANCI heterodimer and activation of DNA damage repair processes. Abbreviations: Ub, ubiquitination.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3974572&req=5

fig-001: Fanconi anemia (FA) signaling is essential for DNA damage repair in interphaseDNA damage in interphase due to genotoxic stress stimulates the DNA damage kinase network, which triggers assembly of the FA core complex followed by monoubiquitination of the FANCD2/FANCI heterodimer and activation of DNA damage repair processes. Abbreviations: Ub, ubiquitination.
Mentions: All known FA proteins work in concert to control the DNA damage response (Fig. 1). Disrupted chromatin activates a network of kinases (including ATR and CHK1) to engage DNA damage pathways and arrest the cell cycle until the lesions are removed from the genome [43]. Some FA proteins are essential for this initial step in damage signal transduction: FANCM activates ATR [44] and CHK1 [45], and FANCJ promotes ATR-mediated cell cycle checkpoint signaling [46]. In return, ATR and CHK1 phosphorylate FANCA, FANCE, and FANCM [47-50]. This positive feedback loop connects the DNA damage kinases and FA proteins to amplify the DNA damage recognition signal. This in turn promotes the activation and assembly of the multiprotein FA core complex, which consists of eight FA proteins as well as several accessory proteins [51,52].

Bottom Line: Loss of FA signaling causes chromosome instability by weakening the spindle assembly checkpoint, disrupting centrosome maintenance, disturbing resolution of ultrafine anaphase bridges, and dysregulating cytokinesis.Thus, the FA genes function as guardians of genome stability throughout the cell cycle.These new discoveries may facilitate the development of rational therapeutic strategies for FA and for FA-deficient malignancies in the general population.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Indiana University School of Medicine, Riley Hospital for Children 705 Riley Hospital Drive, Indianapolis, IN 46202 USA ; Division of Pediatric Hematology-Oncology, Indiana University School of Medicine, Riley Hospital for Children 705 Riley Hospital Drive, Indianapolis, IN 46202 USA ; Department of Medical and Molecular Genetics, Wells Center for Pediatric Research 1044 W. Walnut Street, Indiana University School of Medicine, Indianapolis, IN 46202 USA.

ABSTRACT
Fanconi anemia (FA) is a complex heterogenic disorder of genomic instability, bone marrow failure, cancer predisposition, and congenital malformations. The FA signaling network orchestrates the DNA damage recognition and repair in interphase as well as proper execution of mitosis. Loss of FA signaling causes chromosome instability by weakening the spindle assembly checkpoint, disrupting centrosome maintenance, disturbing resolution of ultrafine anaphase bridges, and dysregulating cytokinesis. Thus, the FA genes function as guardians of genome stability throughout the cell cycle. This review discusses recent advances in diagnosis and clinical management of Fanconi anemia and presents the new insights into the origins of genomic instability in FA. These new discoveries may facilitate the development of rational therapeutic strategies for FA and for FA-deficient malignancies in the general population.

No MeSH data available.


Related in: MedlinePlus