Single strand break (SSBs) and base damage lesions which do not distort the helical structure of the DNA are repaired by base excision repair (BER), bulky adducts and cross-linkages are repaired by nucleotide excision repair (NER) (See figure 1 for DNA damage types and appropriate repair routes). Double strand breaks (DSBs) are resolved through a more complex repair mechanisms involving two separate intricate pathways referred to as Non-homologous end-joining (NHEJ) and Homologous recombination (HR)
Figure 1: Forms of DNA damage, their corresponding repair pathways and signalling complexes

TCTP interacts with the component of the sensor complex comprising the ku70/80 complex, MRN and ATM resulting in the Phosphorylation of yH2AX that amplifies the damage and recruitment process. Binding of ku-80/70 and NHEJ activation is predominant at the G1-early S-phase of the cell cycle. Mediating proteins (53BP1 and BRCA1) compete for binding to the damage site to prevent or promote DNA end resection respectively, which determines the repair pathway of choice. Binding of BRCA1 and activation HR is predominant at late S-phase/G2 cell cycle phas
Figure 2(a): A schematic illustration of TCTP involvement in DSB repair signaling through the NHEJ and HR pathways

Execution of downstream events such as cell cycle arrest, apoptosis activation, and DNA recovery by the effector protein. ATM activates CHK2 which further activates p53, CDC25C, CDC25A to generally halt the cell cycle, activate apoptosis
Figure 2(b): A schematic illustration of TCTP involvement in downstream DSB repair signaling through the NHEJ and HR pathways

p53 plays a central role in DNA damage responses (DDRs), which could lead to cell cycle arrest, DNA repair, senescence or apoptosis upon DNA damage induction. DNA damage activates sensor proteins such as ATM and ATR (1). Activated ATM then phosphorylates CHK2 (2) that subsequently is responsible for phosphorylation of p53 (3). Similarity, activated ATR phosphorylates CHK1 (4) that is required for p53 phosphorylation (5). In addition, ATR can also directly phosphorylate p53 (6). P53 represses TCTP transcription through its binding to the p53 responsive element that is present in the TCTP promoter (7). TCTP directly interacts with MDM2 and stabilizes MDM2 (8), which results in increasing the MDM2-mediated ubiquitination of P53 and therefore p53 downregulation (9). P53 also promotes MDM2 expression by binding to its promoter (10)
Figure 3: A scheme of P53 – TCTP pathway during DNA repair

Antisense Oligonucleotide (ASO) targeting TCTP (called TCTP-ASO) is associated with a carrier (1), facilitating its cellular delivery. Alternatively, Lipid-modified TCTP ASO (TCTP-LASO) can be self- assembled into nanomicelle (2) which can encapsulate with a DNA damage poisoner (3) and go through the cell without delivery-aid (4). Inside the cell, ASO and LASO and encapsulated drugs can be released (5). ASO and LASO hybrid to the specific sequence of TCTP pre-mRNAs or mRNAs (6), leading to downregulation of TCTP protein (7). In addition, other small molecules (such as Sertraline and Thioridazine) also can be used to decrease TCTP protein level (8). These TCTP inhibitors (including TCTP-ASO and small molecules) can be used in parallel with DNA damage caused therapies (Irradiation, chemo drugs). On the other hand, the encapsulated DNA damage chemo-drugs released from the nanomicelles can induce DNA damages (9), which subsequently triggers DNA damage responses (DDRs) (10). TCTP downregulation interrupts DDRs (11), thereby blocking cell cycle arrest and DNA repair, promoting Apoptosis/Senescence, leading to decrease in possibilities of mutagenesis/cancer progression and treatment resistances (12)
Figure 4: Strategies of combinatorial treatment with TCTP inhibitors and DNA poisoners