**7. Conclusion**

*DNA - Damages and Repair Mechanisms*

for survival is genomic instability [104].

**6.2 Targets for cancer therapy**

**Cancer Genetic Background Drug targets Altered** 

NHEJ. This causes shift towards the A-NHEJ for DSB repair [105].

which suggests A-NHEJ mediated genomic instability was suppressed with the help of RAG1/2 proteins and NHEJ factors [94, 95]. RAG complex formed post cleavage shunts the broken ends of DNA to NHEJ thus suppressing recombination events. It is seen that RAG mediated DSB repair during CSR is not compromised in cells lacking NHEJ but is shifted to A-NHEJ [82, 96, 97]. There is effect of absence of DNA-PKcs and it uses Lig1 or Lig3.XRCC1 which acts together with Lig3 is not necessary for A-NHEJ during CSR. Infect the absence of these components increases CSR efficiency [98, 99]. PARP1 and PARP2 is nonessential component during CSR but PARP1 favors A-NHEJ whereas PARP2 suppress translocation during CSR [100]. It is very interesting to note that in chronic myelogenous leukemia (CML) there is increased production of ROS due to increased cell division which is facilitated by BCR-ABL tyrosine kinase. Increased ROS inside the cells leads to DNA damages especially DSB. This leads to the up-regulation of A-NHEJ [101–103]. The cells which are BCR-ABL positive CML shows up regulation of key proteins for A-NHEJ i.e. Lig3α and WRN whereas down regulation of key proteins of NHEJ Artemis and Lig4. Therefore A-NHEJ enables the cells of CML to repair ROS induced DSB and survive. Though this repair pathway of A-NHEJ is error prone the price the cells pay

In acute myeloid leukemia (AML) mutation that occurs are internal tandem duplication (ITD) of FMS-like tyrosine kinase3 (FLT3) receptor. FLT3-ITD is type of cancer which utilizes microhomology mediated A-NHEJ to repair double strand breaks. It causes increased number of deletion. The cells expressing FLT3-ITD has increased protein level of Lig3α but decreased level of Ku protein required for

PARP1 inhibitors could act as therapeutics for cancer in BRCAness (**Table 2**). Certain therapeutic strategy involves the use of DNA ligase as targets [106]. In BCR-ABL-positive CML it is treated with tyrosine kinase inhibitor Imatinib, this strategy immense hope for targeting A-NHEJ factors for therapeutics. Tobin et al. reported that BCR-ABL-positive CML resistant to Imatinib were sensitive to combinational treatment of Ligase and PARP inhibitors which correlates with hyperactive A-NHEJ [109]. This therapy was effective in therapy resistant breast cancer cell lines as it became

> Reduced DNA LIG4, Enhanced DNA LIG3a and

BCR-ABL, enhanced expression of LIG3a, PARP1, and WRN

BRCA 2 deficient

*Disease, impaired repair pathway along with their therapeutic targets.*

PARP1

Breast, Ovarian BRCA 1 deficient

**Repair pathway**

PARP1 with DNA ligase inhibitors

PARP1 with DNA ligase inhibitors

XRCC4 deficient unknown NHEJ [56–59, 73, 74]

KU, P53 deficient Unknown NHEJ [49, 53, 58, 79,

PARP 1 PARP 1 **References**

NHEJ [25, 106, 107]

HR [72, 102, 108]

105]

HR [38, 106]

**110**

**Table 2.**

MCF7 breast cancer

Chronic Myeloid leukemia

Non-BRCA1/2 breast cancer

Leukemia, proBcell lymphoma

Radiation and other assaults that cause DNA damage leading to double strand break are dealt by the mammalian system by relying on tightly regulated repair pathways that are end-joining or recombination-based repair pathways. These are highly regulated repair pathways and results in accurate restoration of the genome. Error prone double strand break repair is still prevalent despite of its mutagenic potential. We must also understand that it is not simply a backup mechanism that comes into play when accurate repair pathway is not possible. The various factors that regulate it are cell cycle stage, local sequence context (homology), and genome structure. So the error prone repair pathway is also very important as it prevents major genome catastrophe. Detailed survey of literature puts forward the fact that error prone pathway paves way for genome evolution in somatic tissues in context of cancer. It is apparent that clear understanding of how A-NHEJ operates and is regulated inside the cell after double strand break will have important therapeutic implication in context of cancer treatment and cure.
