Abstract
The Fanconi anemia (FA) DNA repair pathway coordinates a faithful repair mechanism for stalled DNA replication forks caused by factors such as DNA interstrand crosslinks (ICLs) or replication stress. An important role of FA pathway activation is initiated by monoubiquitination of FANCD2 and its binding partner of FANCI, which is regulated by the ATM-related kinase, ATR. Therefore, regulation of the FA pathway is a good example of the contribution of ATR to genome stability. In this short review, we summarize the knowledge accumulated over the years regarding how the FA pathway is activated via phosphorylation and monoubiquitination.
Highlights
Fanconi anemia (FA) is a rare human genetic disorder characterized by bone marrow failure, skeletal malformation, and increased incidence of cancer
FANCI phosphorylation by ATR kinase was proposed to be a molecular switch to turn on FANCD2 monoubiquitination, which is a landmark of FA pathway activation [16]
Recent studies have revealed additional evidence that S557, S560, and S565 of human FANCI residues are the direct phosphorylation target of ATR kinase, and phosphorylation of these by ATR influences the both rate of FANCD2 ubiquitination and deubiquitination to reveal how monoubiquitinated FANCD2 is maintained at DNA damage sites
Summary
Fanconi anemia (FA) is a rare human genetic disorder characterized by bone marrow failure, skeletal malformation, and increased incidence of cancer. Tan et al reported that using their reconstituted purified protein systems, the phosphatase-treated I-D2 complex eliminated the monoubiqutination of FANCI and FAN CD2, but the addition of recombinant ATR-ATRIP kinase restored the monoubiqutnation level of both proteins [28]. These three residues are the substrates of ATR kinase, and are required for optimal monoubiquitination of FANCI and FANCD2. DNA, which is similar to the crystal structure of a mouse I-D2 complex without DNA [31], ubiquitination induces the rotation of FANCD2, which brings FANCD2 closer to FANCI
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