**1. Introduction**

Cells ability to faithfully repair DNA from insults from endogenous or exogenous sources is essential to maintain viability. Different kinds of damage arise from different sources and require specific DNA repair pathways, allowing recovery of the original sequence. Damage left unrepaired could be inherited after cell division, causing permanent genetic alteration. Accumulation of these mutations leads to cell senescence or apoptosis and may predispose to cancer development.

A complex network of sensors and effectors regulates DNA repair, which starts from the recognition of the damage on DNA to the choice of the most feasible repair pathway, depending on the type of damage and cell cycle phase. Among the various DNA repair pathways, we can distinguish: the base excision repair (BER) and the nucleotide excision repair (NER) primarily involved in removing small, non-helix-distorting base lesions from the genome and to repair bulky helix-distorting lesions and inter-strands crosslinks in G0/G1 phase, respectively [1,2]; the Fanconi anemia (FA) pathway acting during DNA replication for the repair of inter-strand crosslinks [3]; the mismatch repair (MMR) which is a system recognizing and repairing erroneous insertion, deletion, and mis-incorporation of bases [4]; the translesion DNA synthesis (TLS) which is a process that allows DNA replication machinery to replicate past DNA lesions by switching to specialized DNA polymerases [5]; the error-prone non-homologous end joining (NHEJ), which repairs DNA double strand breaks (DSBs) without the requirement of complementary strand [6]; the homologous recombination (HR) which faithfully repairs

DSBs taking advantage of the sequence present on the complementary strand of the homologous chromosome or chromatid, acting in S and G2 cell cycle phases [7]. Moreover, DSBs can also be repaired by the annealing of short (1-few bp) or long (>100 bp) complementary sequences through the highly mutagenic MMEJ (microhomology-mediated end-joining, also known as alternative non-homologous end-joining or Alt-NHEJ), and single strand annealing (SSA), respectively [8,9]. Despite the specificity of each pathway for particular DNA damage and cell cycle phase, none of them are mutually exclusive and they form a network that involves proteins determining the repair outcomes. Mutations affecting the numerous players of these mechanisms could lead to an accumulation of unfaithfully repaired DNA, thus predisposing to cancer development. Moreover, alterations in processes that support genome integrity in normal cells, allow cancer cells to acquire aggressiveness and facilitate the emergence of resistance to DNA damaging cancer treatments [10]. Nevertheless, understanding the emerging role of DNA repair pathway deficiency in cancer allows the development of specific drugs targeting the remaining functional pathways, on which cancer cells are strongly dependent for survival and proliferation. This kind of approach is based on the concept of synthetic lethality, which is a genetic interaction between two genes. If the mutation occurs in only one of the two genes, cell viability is not affected; whereas when two genes are simultaneously mutated, cell death occurs [11]. The discovery of many synthetic lethal interactions between proteins involved in DNA repair allowed the development of personalized therapeutic treatments that target specific DNA repair enzymes to kill cancer cells.

Thanks to the advancement of next-generation sequencing technologies, we now have a clearer indication of which DNA repair-related genes are mutated in each specific cancer: for example, some breast and ovarian cancers are characterized by mutations in BRCA1/BRCA2, while alterations in MMR genes such as MSH2 or MLH1 are related to colorectal cancer [12]. Putting this information together with new synthetic lethality interactions, discovered by novel CRISPR/Cas9 screening approaches in human cells [13,14], will allow the development of the most effective therapeutic approaches by production of drugs targeting DNA repair enzymes specific for each pathological situation.

In this review, we will give a brief introduction to DNA damage checkpoints and repair focusing on different players involved in each pathway and describe how their alterations could impact cancer development and aggressiveness. Then, we will describe how these players can be targeted in cancer therapy and the most encouraging drugs under study, focusing on the rationale behind their usage to improve efficacy of classic therapy or induce specific synthetic lethal interactions.
