[Frontiers in Bioscience 15, 1131-1149, June 1, 2010]

Assembling an orchestra: Fanconi anemia pathway of repair

Fenghua Yuan1, Limin Song1, Liangyue Qian1, Jennifer J. Hu1,2, Yanbin Zhang1

1Department of Biochemistry and Molecular Biology, 2Department of Epidemiology and Public Health, University of Miami Miller School of Medicine, Miami, FL 33136, USA

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Fanconi anemia core complex - Composer, conductor, and musician?
3.1. Components of the FA core complex are phosphorylated under genotoxic stress
3.2. FA core complex is a multi-subunit ubiquitin ligase
3.3. Is FANCM-FAAP24 the only core component that recognizes DNA?
3.4. Functions of FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, and FAAP100
3.4.1. Functions in DNA repair
3.4.2. Functions in mitigating oxidative stress
4. ID complex - Conductor
4.1. ID complex is phosphorylated, monoubiquitinated, and deubiquitinated under genotoxic stress
4.2. ID complex recognizes branched structures
4.3. Functions of the ID complex
5. FANCD1, FANCN, and FANCJ - Musicians
6. Non-FA factors in ICL repair - Guest Musicians
6.1. Endonucleases
6.2. TLS polymerases
6.3. Mismatch repair factors
6.4. Other factors
7. A hypothetical model for FA proteins in ICL repair
8. Conclusion
9. Acknowledgments 10. References

1. ABSTRACT

Fanconi anemia (FA) is a recessive genetic disorder characterized by developmental defects, bone marrow failure, and cancer susceptibility. The complete set of FA genes has only been identified recently and seems to be uniquely conserved among vertebrates. Fanconi anemia proteins have been implicated in the repair of interstrand DNA crosslinks that block DNA replication and transcription. Although all thirteen FA complementation groups show similar clinical and cellular phenotypes, approximately 85% of patients presented defective FANCA, FANCC, or FANCG. The established DNA interacting components (FANCM, FANCI, FANCD2, and FANCJ) account only for ~5% of all FA patients, an observation that raises doubt concerning the roles of FA proteins in DNA repair. In recent years, rapid progress in the area of FA research has provided great insights into the critical roles of FA proteins in DNA repair. However, many FA proteins do not have identifiable domains to indicate how they contribute to biological processes, particularly DNA repair. Therefore, future biochemical studies are warranted to understand the biological functions of FA proteins and their implications in human diseases.