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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

Protein schematic of FANCJ orthologs. C. elegans DOG-1, 983 aa, chicken FANCJ, 1252 aa and human, 1243 aa FANCJ proteins illustrating the position of the conserved DEAD Box (DEXDc) and helicase (HELICc) domains. The BRCA-1 interaction domain of human FANCJ is illustrated (BID). A full protein sequence alignment of DOG-1 and human FANCJ is shown in [8].
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fig2: Protein schematic of FANCJ orthologs. C. elegans DOG-1, 983 aa, chicken FANCJ, 1252 aa and human, 1243 aa FANCJ proteins illustrating the position of the conserved DEAD Box (DEXDc) and helicase (HELICc) domains. The BRCA-1 interaction domain of human FANCJ is illustrated (BID). A full protein sequence alignment of DOG-1 and human FANCJ is shown in [8].

Mentions: In human cell lines, monoubiquitinlation of FANCD2 is followed by HR repair. During S phase, ICLs can block replication; consequently, HR and TLS are required to stabilize the fork and restart replication (reviewed in [18]). In C. elegans, HR repair alleviates the loss of DOG-1. DOG-1 does not function directly in DSB repair, however, as it is not sensitive to radiation-induced DSBs [8]. Bridge et al. determined that FANCJs role in ICL repair is independent of BRCA1 function by demonstrating rescue of FANCJ phenotypes in DT40 cells with the expression of human FANCJ/BRIP1 lacking its BRCA1-interaction domain [17]. Since DOG-1, like the avian FANCJ, does not contain the BRCA-1 interaction domain found in human FANCJ (Figure 2), we infer that the helicase function of DOG-1 is not required for HR-mediated DSB repair following replication block or ICL induction.


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

Jones M, Rose A - Anemia (2012)

Protein schematic of FANCJ orthologs. C. elegans DOG-1, 983 aa, chicken FANCJ, 1252 aa and human, 1243 aa FANCJ proteins illustrating the position of the conserved DEAD Box (DEXDc) and helicase (HELICc) domains. The BRCA-1 interaction domain of human FANCJ is illustrated (BID). A full protein sequence alignment of DOG-1 and human FANCJ is shown in [8].
© Copyright Policy
Related In: Results  -  Collection

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

fig2: Protein schematic of FANCJ orthologs. C. elegans DOG-1, 983 aa, chicken FANCJ, 1252 aa and human, 1243 aa FANCJ proteins illustrating the position of the conserved DEAD Box (DEXDc) and helicase (HELICc) domains. The BRCA-1 interaction domain of human FANCJ is illustrated (BID). A full protein sequence alignment of DOG-1 and human FANCJ is shown in [8].
Mentions: In human cell lines, monoubiquitinlation of FANCD2 is followed by HR repair. During S phase, ICLs can block replication; consequently, HR and TLS are required to stabilize the fork and restart replication (reviewed in [18]). In C. elegans, HR repair alleviates the loss of DOG-1. DOG-1 does not function directly in DSB repair, however, as it is not sensitive to radiation-induced DSBs [8]. Bridge et al. determined that FANCJs role in ICL repair is independent of BRCA1 function by demonstrating rescue of FANCJ phenotypes in DT40 cells with the expression of human FANCJ/BRIP1 lacking its BRCA1-interaction domain [17]. Since DOG-1, like the avian FANCJ, does not contain the BRCA-1 interaction domain found in human FANCJ (Figure 2), we infer that the helicase function of DOG-1 is not required for HR-mediated DSB repair following replication block or ICL induction.

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