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A DOG's View of Fanconi Anemia: Insights from C. elegans.

Jones M, Rose A - Anemia (2012)

Bottom Line: When DOG-1 is absent but crosslinking agents are present the G-rich structures are readily covalently crosslinked, resulting in increased crosslinks formation and thus giving increased crosslink sensitivity.In this interpretation DOG-1 is neither upstream nor downstream in the FA pathway, but works alongside it to limit the availability of crosslink substrates.This model reconciles the crosslink sensitivity observed in the absence of DOG-1 function with its unique role in maintaining G-Rich DNA and will help to formulate experiments to test this hypothesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V6T 1Z4.

ABSTRACT
C. elegans provides an excellent model system for the study of the Fanconi Anemia (FA), one of the hallmarks of which is sensitivity to interstrand crosslinking agents. Central to our understanding of FA has been the investigation of DOG-1, the functional ortholog of the deadbox helicase FANCJ. Here we review the current understanding of the unique role of DOG-1 in maintaining stability of G-rich DNA in C. elegans and explore the question of why DOG-1 animals are crosslink sensitive. We propose a dynamic model in which noncovalently linked G-rich structures form and un-form in the presence of DOG-1. When DOG-1 is absent but crosslinking agents are present the G-rich structures are readily covalently crosslinked, resulting in increased crosslinks formation and thus giving increased crosslink sensitivity. In this interpretation DOG-1 is neither upstream nor downstream in the FA pathway, but works alongside it to limit the availability of crosslink substrates. This model reconciles the crosslink sensitivity observed in the absence of DOG-1 function with its unique role in maintaining G-Rich DNA and will help to formulate experiments to test this hypothesis.

No MeSH data available.


Related in: MedlinePlus

A model for DOG-1 function in genome stability and ICL response. The left panel illustrates DOG-1's role in G-tract maintenance. G4 formation on the lagging strand is resolved by the helicase function of DOG-1 and replication proceeds efficiently. In the absence of DOG-1 HR mediated by the FA pathway resolves a subset of stalled forks. Repair utilizing the mutagenic NHEJ repair mechanism results in deletions. The right panel describes a possible model for DOG-1 ICL sensitivity. In the presence of DOG-1, G4 structures may be resolved and not available as substrate for ICL stabilization. In the absence of DOG-1 G4 structures are available as substrate for ICL stabilization leading to an in increase in fork stalling, which is interpreted as an ICL sensitivity phenotype.
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fig3: A model for DOG-1 function in genome stability and ICL response. The left panel illustrates DOG-1's role in G-tract maintenance. G4 formation on the lagging strand is resolved by the helicase function of DOG-1 and replication proceeds efficiently. In the absence of DOG-1 HR mediated by the FA pathway resolves a subset of stalled forks. Repair utilizing the mutagenic NHEJ repair mechanism results in deletions. The right panel describes a possible model for DOG-1 ICL sensitivity. In the presence of DOG-1, G4 structures may be resolved and not available as substrate for ICL stabilization. In the absence of DOG-1 G4 structures are available as substrate for ICL stabilization leading to an in increase in fork stalling, which is interpreted as an ICL sensitivity phenotype.

Mentions: We propose the following model as a resolution of this apparent paradox (Figure 3). G4 structures are known to form in a variety of circumstances as proposed by Wu et al. [22], which could include within a single strand of DNA, between DNA strands and between strands on separate chromosomes. The latter resulting in chromosomal translocations if not repaired correctly. In the absence of crosslinking agents, these secondary structures can form and unform depending upon the availability of DOG-1. In the C. elegans genome, there are nearly 400 poly-G regions distributed along each of the chromosomes and this pattern of distribution is conserved in a related nematode [23] providing a rich source of substrate for DOG-1. In the presence of a crosslinking agent, many of which have affinity for G's, secondary structures formed by these G-rich regions might be targets for covalent crosslinking. Here we suggest that once the secondary structures are detected by FA pathway components the first responder is DOG-1. The pathway detector may not distinguish between a noncovalent secondary structure and a crosslink. If the structure is not covalently linked, DOG-1 resolves it. If it is covalently linked, and not resolved by DOG-1, FA pathway-directed TLS and HR repair the lesion. In the absence of DOG-1, there is likely to be an increase in stabilized G-rich structures that may be beyond the ability of the FA pathway to respond to, giving the appearance of a crosslink sensitive phenotype. Further experiments will be needed to move towards a more complete understanding of the crosstalk among FA proteins.


A DOG's View of Fanconi Anemia: Insights from C. elegans.

Jones M, Rose A - Anemia (2012)

A model for DOG-1 function in genome stability and ICL response. The left panel illustrates DOG-1's role in G-tract maintenance. G4 formation on the lagging strand is resolved by the helicase function of DOG-1 and replication proceeds efficiently. In the absence of DOG-1 HR mediated by the FA pathway resolves a subset of stalled forks. Repair utilizing the mutagenic NHEJ repair mechanism results in deletions. The right panel describes a possible model for DOG-1 ICL sensitivity. In the presence of DOG-1, G4 structures may be resolved and not available as substrate for ICL stabilization. In the absence of DOG-1 G4 structures are available as substrate for ICL stabilization leading to an in increase in fork stalling, which is interpreted as an ICL sensitivity phenotype.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368526&req=5

fig3: A model for DOG-1 function in genome stability and ICL response. The left panel illustrates DOG-1's role in G-tract maintenance. G4 formation on the lagging strand is resolved by the helicase function of DOG-1 and replication proceeds efficiently. In the absence of DOG-1 HR mediated by the FA pathway resolves a subset of stalled forks. Repair utilizing the mutagenic NHEJ repair mechanism results in deletions. The right panel describes a possible model for DOG-1 ICL sensitivity. In the presence of DOG-1, G4 structures may be resolved and not available as substrate for ICL stabilization. In the absence of DOG-1 G4 structures are available as substrate for ICL stabilization leading to an in increase in fork stalling, which is interpreted as an ICL sensitivity phenotype.
Mentions: We propose the following model as a resolution of this apparent paradox (Figure 3). G4 structures are known to form in a variety of circumstances as proposed by Wu et al. [22], which could include within a single strand of DNA, between DNA strands and between strands on separate chromosomes. The latter resulting in chromosomal translocations if not repaired correctly. In the absence of crosslinking agents, these secondary structures can form and unform depending upon the availability of DOG-1. In the C. elegans genome, there are nearly 400 poly-G regions distributed along each of the chromosomes and this pattern of distribution is conserved in a related nematode [23] providing a rich source of substrate for DOG-1. In the presence of a crosslinking agent, many of which have affinity for G's, secondary structures formed by these G-rich regions might be targets for covalent crosslinking. Here we suggest that once the secondary structures are detected by FA pathway components the first responder is DOG-1. The pathway detector may not distinguish between a noncovalent secondary structure and a crosslink. If the structure is not covalently linked, DOG-1 resolves it. If it is covalently linked, and not resolved by DOG-1, FA pathway-directed TLS and HR repair the lesion. In the absence of DOG-1, there is likely to be an increase in stabilized G-rich structures that may be beyond the ability of the FA pathway to respond to, giving the appearance of a crosslink sensitive phenotype. Further experiments will be needed to move towards a more complete understanding of the crosstalk among FA proteins.

Bottom Line: When DOG-1 is absent but crosslinking agents are present the G-rich structures are readily covalently crosslinked, resulting in increased crosslinks formation and thus giving increased crosslink sensitivity.In this interpretation DOG-1 is neither upstream nor downstream in the FA pathway, but works alongside it to limit the availability of crosslink substrates.This model reconciles the crosslink sensitivity observed in the absence of DOG-1 function with its unique role in maintaining G-Rich DNA and will help to formulate experiments to test this hypothesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada V6T 1Z4.

ABSTRACT
C. elegans provides an excellent model system for the study of the Fanconi Anemia (FA), one of the hallmarks of which is sensitivity to interstrand crosslinking agents. Central to our understanding of FA has been the investigation of DOG-1, the functional ortholog of the deadbox helicase FANCJ. Here we review the current understanding of the unique role of DOG-1 in maintaining stability of G-rich DNA in C. elegans and explore the question of why DOG-1 animals are crosslink sensitive. We propose a dynamic model in which noncovalently linked G-rich structures form and un-form in the presence of DOG-1. When DOG-1 is absent but crosslinking agents are present the G-rich structures are readily covalently crosslinked, resulting in increased crosslinks formation and thus giving increased crosslink sensitivity. In this interpretation DOG-1 is neither upstream nor downstream in the FA pathway, but works alongside it to limit the availability of crosslink substrates. This model reconciles the crosslink sensitivity observed in the absence of DOG-1 function with its unique role in maintaining G-Rich DNA and will help to formulate experiments to test this hypothesis.

No MeSH data available.


Related in: MedlinePlus