DNA Repair: Exploiting the Fanconi Anemia Pathway As a Potential Therapeutic Target

Abstract

DNA repair is an active cellular process to respond to constant DNA damage caused by metabolic processes and environmental factors. Since the outcome of DNA damage is generally adverse and long term effects may contribute to oncogenesis, cells have developed a variety of DNA repair mechanisms, which operate depending on the type of DNA damage inflicted. At least 15 Fanconi anemia (FA) proteins interact in a common pathway involved in homologous recombination. Inherited homozygous mutations in any of these FA genes cause a rare disease, Fanconi anemia, characterized by congenital abnormalities, progressive bone-marrow failure and cancer susceptibility. Heterozygous germline FA mutations predispose to various types of cancer. In addition, somatic FA mutations have been identified in diverse cancer types. Evidence exists that cells deficient in the FA pathway become dependent on alternative pathways for survival. Additional inhibition of such alternative pathways is thus expected to result in cell death, creating a relationship of synthetic lethality. Identifying these relationships can reveal yet unknown mechanisms of DNA repair and new targets for therapy.

Inactivation of BRCA2 in human cancer cells identifies a subset of tumors with enhanced sensitivity towards death receptormediated apoptosis

“…The DNA repair system represents a central mechanism of cellular homeostasis facilitating the detection and consequent repair of exogenous and endogenous DNA damage, thus preventing the perpetuation of potentially detrimental mutations and cancer formation. It consists of multiple DNA repair mechanisms which, depending on the recognized DNA damage pattern and cell cycle phase, activate different DNA repair pathways [ 1 , 2 ]. Upon recognition of DNA damage, a complex system of events is triggered to restore genetic integrity.…”

Microphthalmos, orbital cyst, and missing thumbs: A rare case report

“…Hematopoietic growth factors, androgen therapy, bone marrow transplantation, preimplantation genetic diagnosis and prevention, surveillance, early detection, and treatment of malignancies are general standards of care for FA patients from a physician's point of view. [ 3 ] The mean survival age is about 16 years. The increased susceptibility to malignancies leads to the grave biological course for children suffering from FA.…”

“…[ 2 ] DNA repair disorder leads to chromosomal instability causing increased mutagenesis, accumulation of DNA damage, increased susceptibility to exogenous DNA damaging agents, and induces the apoptosis of hematopoietic stem cells resulting in their depletion. [ 3 ] Fifteen FANC genes have been identified so far, the most prevalent being FANCA, FANCC, FANCG, and FANCD2. [ 4 ]…”

Deubiquitylating Enzymes and DNA Damage Response Pathways

“…BRCA1/2 mutation carriers also show increased risks of developing other cancer types, including prostate, pancreatic and stomach cancers [23,24]. FA is another disease where mutations in one of fifteen FA genes lead to defects in DNA inter-strand cross-link (ICL) repair, and HR is associated with increased cancer incidence [25,26].…”

“…DUBs regulating the processes of HR, NHEJ, NER, BER, TLS, FA, mismatch repair and checkpoint control have been identified (Table 1). Moreover, examples of synthetic lethality interaction between DDR pathways clearly identified as mutated in tumours but fully functional in normal cells have triggered a plethora of screening approaches for the identification of novel therapeutic opportunities [26,[184][185][186][187], which may include DUBs. In addition, many DUBs have been linked to cancer pathways that have not been linked to DDR pathways, thus further broadening the scope for DUB inhibitors in oncology [37,51,57].…”