Research progress of the Fanconi anemia pathway and premature ovarian insufficiency

Abstract

The Fanconi anemia pathway is a key pathway involved in the repair of deoxyribonucleic acidinterstrand crosslinking damage, which chiefly includes the following four modules: lesion recognition, Fanconi anemia core complex recruitment, FANCD2–FANCI complex monoubiquitination, and downstream events (nucleolytic incision, translesion synthesis, and homologous recombination). Mutations or deletions of multiple Fanconi anemia genes in this pathway can damage the interstrand crosslinking repair pathway and disrupt primordial germ cell development and oocyte meiosis, thereby leading to abnormal follicular development. Premature ovarian insufficiency is a gynecological clinical syndrome characterized by amenorrhea and decreased fertility due to decreased oocyte pool, accelerated follicle atresia, and loss of ovarian function in women <40 years old. Furthermore, in recent years, several studies have detected mutations in the Fanconi anemia gene in patients with premature ovarian insufficiency. In addition, some patients with Fanconi anemia exhibit symptoms of premature ovarian insufficiency and infertility. The Fanconi anemia pathway and premature ovarian insufficiency are closely associated.

Pharmacogenomic studies of fertility outcomes in pediatric cancer survivors – A systematic review

“…For example, cancer patients who carry mutations in DNA repair genes, for example BRCA1, BRCA2, may be more susceptible to alkylator damage, 37 , 38 , 39 , 40 , 41 , 42 , 43 and patients with variants of DNA repair genes, such as NBN, MCM8/9 likely have elevated risk of infertility and cancer independent of therapy. 14 , 58 , 59 , 60 Repair mechanisms are limited, increasing cytotoxicity and the risk of further mutagenesis. The unique nature of each clinical case highlights the need for a well‐represented cohort for analysis, including heterogeneity with respect to ethnicity and disease state.…”

“…In addition, women with NBS, Fanconi anemia or MCM8/9 variants are at greater risk for both POI and cancer development. 14 , 58 , 59 , 60 For men, it was found that the ERCC1 gene, which is associated with glioblastoma and oral squamous cell carcinoma cancer, was significantly associated with azoospermia. 21 In addition, the inactivation or sub‐function of GPRC6A, which is associated with prostate cancer, was reported to lead to low sperm counts in adulthood.…”

“…Also, BRCA1 37–42 and BRCA2 mutations, 43 which are associated with breast and ovarian cancers, are also associated with POI. In addition, women with NBS, Fanconi anemia or MCM8/9 variants are at greater risk for both POI and cancer development 14,58–60 . For men, it was found that the ERCC1 gene, which is associated with glioblastoma and oral squamous cell carcinoma cancer, was significantly associated with azoospermia 21 .…”

BRCA Mutations and Fertility Preservation

“…Its interaction with BARD1 promotes the phosphorylation of p53 by ATM, leading to the transcription of p21 and cell cycle arrest in the G1 phase. Through its interaction with BRIP1 (also known as FANCJ) [ 45 , 46 ] and DNA topoisomerase 2-binding protein 1 (TOPBP1), BRCA1 facilitates CHK1 phosphorylation by ATM. Phosphorylated CHK1 activates WEE1 and inhibits M-phase inducer phosphatase 1–3 (CDC25A-C).…”

“…BRCA2 is mainly involved in DNA repair through HR but is also involved in intra-strand crosslinks (ICLs) [ 46 ] and programmed DSBs during meiosis. Moreover, it has also been shown that BRCA2 is involved in the protection of telomere integrity and stalled replication fork degradation.…”