Finally, AZD7648 was described as a potent and highly specific DNA-PK inhibitor, having promising application in combination with standard therapies . AsiDNA is a first-in-class DNA repair inhibitor that functions on enzymes involved in different DNA repair pathways, as HR, NHEJ, BER and SSA, providing an extensive DNA repair inhibitory activity rather than targeting specific DSBs proteins . Small molecule inhibitors of MRN complex, RAD51, RAD52 and RAD54 have also been designed for targeting DSBs repair (Table 1 and Table 2). of resistance due to multi-connected DNA repair pathways that may compensate for each other. Hence, the search for additional effective brokers targeting DNA damage repair (DDR) is usually of crucial importance. In this context, BRCA1 has assumed a central role in developing drugs aimed at inhibiting DNA repair activity. Collectively, this review provides an in-depth understanding of the biology and regulatory mechanisms of DDR pathways, highlighting the potential of DDR-associated molecules, particularly BRCA1 and its interconnected partners, in precision malignancy medicine. It also affords an overview about what we have achieved and a reflection on how much remains to be done in this field, further addressing encouraging clues for the advance of DDR targeted therapy. germline mutations account for most known heritable forms of cancer such as hereditary breast and ovarian malignancy (HBOC) syndrome . Despite the increased risk ERK5-IN-1 conferred by mutations to malignancy onset, pre-clinical and clinical data have ascertained that BRCA1 impairment is commonly associated with chemosensitivity in malignancy cells [13,16]. ERK5-IN-1 BRCA1 has therefore become an important predictive and therapeutic molecule for developing targeted anticancer strategies. Other players involved in DDR can also be found defective in malignancy, including breast malignancy susceptibility gene 2 ((located on chromosome 17) was identified as a classical tumour suppressor gene (TSG) due to the loss of a wild-type (wt) allele during tumorigenesis, being the first TSG associated with hereditary and sporadic cases of basal-like breast malignancy [25,26]. Despite being a multifunctional protein, the BRCA1 tumour suppressive function is mainly ensured by its ability to maintain genomic Rabbit Polyclonal to PPP2R3C integrity through regulation of diverse cellular processes, including DDR, cell cycle checkpoint, apoptosis, chromosome instability, among others [16,17]. The BRCA1 effect on DDR seems to mainly occur through regulation of homologous recombination (HR)  (Physique 1). In fact, most mutant BRCA1 (BRCA1Mut) forms are defective in HR activity, although in varying grades depending on the location of the mutation . Although poorly understood, BRCA1 may also participate in non-homologous end joining (NHEJ), alternate NHEJ, and single-strand annealing (SSA) repair pathways [8,28]. Upon DNA damage, the opposite functions played by p53-binding protein 1 (53BP1) and BRCA1 seem to support cells in the switch between NHEJ and HR . However, this mechanism is not completely comprehended . Studies have also revealed that BRCA1 interacts with Ku80 (a crucial protein in NHEJ), being recruited to DSBs sites in a Ku80-dependent manner . In fact, DNA repair pathways compete to select which mechanism should be employed. This choice is based on several factors, including cell cycle phase. Somatic cells use error-prone NHEJ as a major DSBs repair mechanism throughout all cell cycle stages, but particularly occurring in G1 phase, while HR is employed predominantly in S to G2 phases . The gene has 24 exons, two of them untranslated, and encodes a large 1863-amino acid phosphoprotein that harbours multiple functional domains, including the highly conserved gene is composed by a centrally located exon 11, which encodes two NLS and binding sites for several proteins [32,33] (Physique 2). This is one of the largest human exons (encoding 1142 amino acids) that partially contributes to BRCA1 nuclear localization and activity on cell cycle regulation and DNA repair, being highly required for a functional HR [34,35]. Together with exons ERK5-IN-1 12 and 13, exon 11 encodes a coiled-coil domain name that mediates interactions with PALB2 and a serine cluster domain name (SCD) that is phosphorylated by ATM and ATR [32,33]. Pathogenic mutations in exons 11-13 are frequently detected in breast and ovarian malignancy patients, which reinforces the relevance of these exons in tumour suppression [32,33]. Open in a separate window Physique 2 Structural business of BRCA1 with respective interacting proteins and most prevalent mutations. Full length BRCA1 contains two conserved domains at its termini: , such as frameshift insertions/deletions, nonsense truncation mutations that lead to premature chain termination, and many single nucleotide polymorphisms in the coding or noncoding sequences. Over 70C80% of BRCA1 mutations result in dysfunctional or absent protein product. Also, a number of missense BRCA1 mutations present clinical relevance, being associated with increased risk of both hereditary and sporadic cancers.