RAD51 as a potential surrogate marker for DNA repair capacity in solid malignancies

Abstract

Targeting deficient mechanisms of cellular DNA repair still represents the basis for the treatment of the majority of solid tumors, and increased DNA repair capacity is a hallmark mechanism of resistance not only to DNA-damaging treatments such as cytotoxic drugs and radiotherapy, but also to small molecule targeted drugs such as inhibitors of poly-ADP ribose polymerase (PARP). Hence, there is substantial medical need for potent and convenient biomarkers of individual response to DNA-targeted treatment in personalized cancer care. RAD51 is a highly conserved protein that catalyzes DNA repair via homologous recombination, a major DNA repair pathway which directly modulates cellular sensitivity to DNA-damaging treatments. The clinical and biological significance of RAD51 protein expression is still under investigation. Pre-clinical studies consistently show the important role of nuclear RAD51 immunoreactivity in chemo- and radioresistance. Validating data from clinical trials however is limited at present, and some clinical studies show controversial results. This review gives a comprehensive overview on the current knowledge about the prognostic and predictive value of RAD51 protein expression and genetic variability in patients with solid malignancies.

Nucleoporin 54 contributes to homologous recombination repair and post-replicative DNA integrity

“…BRCA1 and BRCA2 ) and their epigenetic status (e.g. BRCA1 silencing) have been linked to an increased risk of developing a variety of cancers (61,62). Deficiencies in HR repair factors are associated with a high sensitivity not only to IR, but also to several other DNA damaging agents and drugs, and are currently exploited in the clinic to guide treatment decisions (61–63).…”

“…Specifically, poly (ADP-ribose) polymerase (PARP) inhibitors are an established and effective treatment for patients with tumours harbouring BRCA mutations (63). A major limitation for the use of known HR deficiencies as biomarkers is the low frequency with which they are found in cancer patients (62). In this regard, the discovery of new factors involved in HR could help to better define the DNA repair capability of tumours and tailor targeted therapies more appropriately.…”

PARP inhibitor Olaparib increases the sensitization to radiotherapy in FaDu cells

“…Ionizing radiation induces several types of DNA damage, including base modifications, crosslinks, single‐strand breaks (SSB) and double‐strand breaks (DSB) . The failure of DNA damage response (DDR) can trigger a permanent cell cycle arrest or programmed cell death . Increased DNA repair capacity is a hallmark of radiotherapy resistance.…”

“…18 The failure of DNA damage response (DDR) can trigger a permanent cell cycle arrest or programmed cell death. 19 Increased DNA repair capacity is a hallmark of radiotherapy resistance. Thus, there is substantial clinical need for potent and effective biomarkers for individual response to radiotherapy.…”

O-Glcnac Glycosylation of Rad51 Plays an Important Role in Promoting Colorectal Cancer Cell Invasion

“…As a key factor in the repair of DNA double-strand breaks through homologous recombination, the existence of Rad51 is very important for the maintenance of genomic stability. Rad51 overexpression leads to the accumulation of abnormal karyotypes and gene mutations, which are closely related to carcinogenesis and drug resistance [16]. Studies have shown that, such as breast cancer, pancreatic cancer and other tumors overexpressed Rad51 protein, positively correlated to tumor histological grade and stage [17,18].…”