FANCD2

FANCD2 (Fanconi Anemia, Complementation Group D2) is a protein that in humans is encoded by the FANCD2 gene. This protein plays a crucial role in the repair of DNA damage and the maintenance of chromosomal stability. The FANCD2 gene is part of a cluster of genes related to Fanconi anemia (FA), a rare genetic disorder that leads to increased risk of cancer and bone marrow failure.

Function

FANCD2 is a key component of the FA/BRCA pathway, a cellular network involved in the repair of DNA interstrand crosslinks (ICLs). ICLs are toxic lesions that prevent DNA strand separation, essential for DNA replication and transcription. The FA/BRCA pathway is activated in response to DNA damage, leading to the monoubiquitination of FANCD2. Monoubiquitinated FANCD2 then localizes to chromatin and coordinates DNA repair processes, including homologous recombination and nucleotide excision repair. This pathway also involves interactions with other proteins, such as BRCA1 and BRCA2, highlighting its importance in tumor suppression and genomic stability.

Clinical Significance

Mutations in the FANCD2 gene are associated with Fanconi anemia, a condition characterized by physical abnormalities, bone marrow failure, and increased cancer risk, particularly acute myeloid leukemia (AML) and head and neck squamous cell carcinomas. The diagnosis of FA is often confirmed through the detection of mutations in FANCD2 or other genes involved in the FA/BRCA pathway. Additionally, FANCD2 has been implicated in the development of sporadic cancers, suggesting its role as a broader tumor suppressor.

Research into FANCD2 has also led to therapeutic insights. For example, cells deficient in FANCD2 are hypersensitive to DNA crosslinking agents, which has implications for the treatment of FA patients and the potential exploitation of FANCD2 pathways in cancer therapy. Targeting the FA/BRCA pathway, including FANCD2, with specific inhibitors can sensitize cancer cells to chemotherapy, offering a strategy for overcoming drug resistance.

Genetic and Molecular Biology

The FANCD2 gene is located on chromosome 3p26.3 and consists of 44 exons. The protein encoded by this gene contains 1451 amino acids and has several important domains for its function in DNA repair, including a nuclear localization signal and a ubiquitin-binding domain. The regulation of FANCD2 involves post-translational modifications, such as ubiquitination and phosphorylation, which are critical for its role in the DNA damage response.

See Also

• Fanconi anemia
• DNA repair
• BRCA1
• BRCA2
• Homologous recombination
• Nucleotide excision repair