Abstract
The Fanconi anemia (FA) pathway plays a central role in the repair of DNA interstrand crosslinks (ICLs) and regulates cellular responses to replication stress. Homologous recombination (HR), the error‐free pathway for double‐strand break (DSB) repair, is required during physiological cell cycle progression for the repair of replication‐associated DNA damage and protection of stalled replication forks. Substantial crosstalk between the two pathways has recently been unravelled, in that key HR proteins such as the RAD51 recombinase and the tumour suppressors BRCA1 and BRCA2 also play important roles in ICL repair. Consistent with this, rare patient mutations in these HR genes cause FA pathologies and have been assigned FA complementation groups. Here, we focus on the clinical and mechanistic implications of the connection between these two cancer susceptibility syndromes and on how these two molecular pathways of DNA replication and repair interact functionally to prevent genomic instability.
Highlights
The Fanconi anemia (FA) family includes 19 distinct functional complementation groups (A, B, C, D1, D2, E, F, G, I, J, L, M, N, O, P, Q, R, S, T) whose gene products suppress interstrand crosslink (ICL) sensitivity
A subset of FA proteins includes the well-characterised RAD51 recombinase, as well as the tumour suppressors BRCA1 and BRCA2, which are directly involved in the homologous recombination (HR) pathway of double-strand break (DSB) repair (Venkitaraman, 2009)
We discuss the roles of FA and HR pathways in the cellular response to exogenous and endogenous sources of DNA damage, and how they impact on telomere and genome integrity
Summary
The Fanconi anemia (FA) family includes 19 distinct functional complementation groups (A, B, C, D1, D2, E, F, G, I, J, L, M, N, O, P, Q, R, S, T) whose gene products suppress interstrand crosslink (ICL) sensitivity. In cells lacking a functional FA pathway, ICLs elicit complex DNA lesions, illegitimately repaired to produce radial chromosomes, which represent the cellular FA signature. These chromosomal aberrations underlie the extreme toxicity of ICL-inducing treatments to FA cells (Auerbach et al, 1989). FA pathologies FA pathologies FA pathologies; not all patients display bone marrow failure; mutation carriers have higher risk of breast and ovarian tumours and lower onset age FA pathologies. FA-like syndrome; patients do not display bone marrow failure; mutation carriers have higher risk of breast and ovarian tumours and lower onset age FA pathologies
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