**1. Introduction**

Mammalian cells face an estimate of 105 genomic injuries every day. These lesions are diverse and can include, among others, single (SSB) and double strand breaks (DSB), oxidative damage, DNA inter- and intra-strand crosslinking, base mismatches, bulky adducts, and photoproducts [1, 2]. This large variety of DNA lesions is directly related to the full range of mutation-causing agents that threaten the genome on a daily basis. Some of these agents are endogenously produced by the cell's own metabolism and homeostasis, while others are generated exogenously. The frequency of appearance of these lesions is also diverse, and it may depend on the cell type or the developmental stage [1]. For instance, skin epithelial cells are much more susceptible to photoproducts caused by ultraviolet rays, an exogenous source of mutations that can only reach the outermost layers of our body. In contrast, reactive oxygen species (ROS) are endogenous metabolic byproducts that can induce oxidative base modifications and SSB, one of the most common genomic injuries. Cells with high energy and metabolic demands are, therefore, most susceptible to suffer SSB-related and other ROS-related injuries.

To defend from the menacing threat that this wide range and number of lesions pose to the integrity of their genome, cells can invoke the DNA damage response (DDR), a vast network of overlapping pathways that is capable of tailoring a response depending on the type and extent of the lesion and the cell cycle stage at the moment of the injury [3–6]. DDR requires the coordination of DNA repair pathways with cell cycle progression regulation, transcription activation, and apoptosis, among other pathways [5, 7, 8].

Somewhat surprisingly, mutations in genes belonging to DDR pathways correlate with neurodevelopmental defects and neurodegenerative pathologies [5, 9–11]. For instance, individuals with dysfunctional versions of SSB repair genes APTX, PNPK, or XRCC1 manifest different types of ataxias with ocular apraxia; whereas, defective TDP1, also involved in SSB repair, can cause spinocerebellar ataxia with axonal neuropathy [9, 12]. Similarly, mutations in DSB repair gene MRE11, or central DDR regulators ATM and ATR, can lead to cerebellar ataxia [5, 13]. Besides ataxias, microcephaly is commonly found linked to defects in several DDR associated genes [1, 5, 14]. Mutations in NBS1 and RAD50, two genes involved in end processing during DSB repair, can cause Nijmegen breakage syndrome (NBS) and NBS-like syndrome, respectively, both syndromes manifesting microcephaly among other conditions [5, 15, 16]. Microcephalia is also present in individuals with dysfunctional PNPK, LIG4—a gene involved in DSB repair—or Seckel Syndrome 1, a developmental disorder caused by some ATR mutations [9, 15]. Furthermore, around 25% of patients with defective nucleotide excision repair (NER)—a DDR pathway in charge of healing photoproducts created by UV light exposure—can also present microcephaly among other neurological problems [5]. Overall, this data suggest a strong and intriguing link between DDR, neurodevelopment, and neuropathology. This review focuses on ATM, its role during DDR, and the molecular basis of ataxia-telangiectasia (A-T), a neurodegenerative syndrome caused by defective or absent ATM.
