**2.5 Other DDR pathways**

ATM and ATR also integrate into DDR several other pathways that are essential to provide an adequate and proportionate response to all kind of injuries. For instance, no proper DDR can occur without the upregulation of dNTP for DNA repair [85]. This upregulation requires tight control, as excessive dNTP production can lead to increased mutation frequency [86]. In the presence of DNA damage, DDR kinases regulate RNR—the kinase that catalyzes rate-limiting step during dNTP production—at multiple levels. For instance, p53 regulates the expression levels of RNR; whereas, ATM phosphorylation increases the stability of RNR [87]. In addition, ATR signaling inhibits degradation of some RNR subunits, further contributing to the regulation of dNTP levels by DDR kinases.

Dysfunctional telomeres can also activate ATM and ATR and elicit a response that includes halting the cell cycle and induction of senescence [88]. Telomere dysfunction can arise when errors in the Shelterin complex render telomeres unprotected. Loss of protection at telomeres can also occur by the natural attrition of telomere length experienced during DNA replication in cells that do not express telomerase [89]. In both cases, DNA ends at telomeres can be mistakenly recognized as DNA damage events and activate DDR.

Recently, activation of autophagy has emerged as another tool that DDR can use to fight severe DNA damage. While autophagy was initially thought to be exclusively activated in response to cellular damage or starvation, there is clear evidence that DNA damage can also trigger autophagy [90]. For instance, the action of mTOR—the main autophagy inhibitor—can be repressed either in an ATM or PARP1 dependent manner following DNA damage, effectively promoting autophagy [7]. Consistent with this, in response to ROS mediated damage, ATM can induce selective degradation of mitochondria by autophagy (also known as

mitophagy) and pexophagy—the autophagic degradation of peroxisomes [91–93]. Integration of autophagy pathways as part of DDR repertoire may allow cells in stress to attempt pro-survival pathways first before succumbing to apoptosis.

While the complex relationships between DDR and inflammation are beginning to emerge, it is clear that ROS and other types of genomic injuries can elicit a proinflammatory response. As part of DDR, this pro-survival cell response is mediated mostly through ATM and PARP1 [94]. ATM directly binds and phosphorylates IKK-γ (NEMO), the regulatory subunit of the IKK complex that activates NF-kB [41]. Along with PARP1-mediated post-translational modifications, ATM phosphorylation of IKK-γ promotes activation of IKK and subsequent activation of NF-kB [41, 95–97]. Therefore, this critical pro-inflammatory enzyme is under DDR control, where it can function as a transcription factor promoting expression of pro-inflammatory cytokines and DNA repair genes [76, 94, 95, 98]. In addition, ATM is involved in a pro-inflammatory pathway known as senescence-associated secretory phenotype (SASP), a complex mechanism that secretes, among others, pro-inflammatory cytokines [94, 99].
