Inadequate DNA repair leads to Increase, Chromosomal aberrations

Cells are exposed to many insults, both endogenous and exogenous, that may cause damage to their DNA. In response to this constant threat, cells have accordingly evolved many different pathways for repairing DNA damage (Pfeiffer & Goedecke, 2000; Hoeijmakers, 2001; Jeggo & Markus, 2015; Rode et al., 2016). When confronted with double strand breaks (DSBs), there are two common repair pathways employed by the cell: homologous recombination (HR) and non-homologous end-joining (NHEJ). In HR, a homologous sequence on the sister chromatid is used as a template, ensuring that no sequence information is lost over the course of repair (Ferguson & Alt, 2001; van Gent et al., 2001; Hoeijmakers, 2001; Jeggo & Markus, 2015; Schipler & Iliakis, 2013; Venkitaraman, 2002). However, this method of DNA repair may result in a loss of an allele leading to heterozygosity. This may occur if a non-homologous chromosome with an erronous sequence is used as the template instead of the homologous chromosome, thus leading to a loss of genetic information (Ferguson & Alt, 2001). Despite this possible error, HR is generally considered to be one of the more accurate methods of DNA repair because it does make use of a template (van Gent et al., 2001; Schipler & Iliakis, 2013; Venkitaraman, 2002) .  NHEJ, however, does not use a template and is generally described as being error-prone. This repair process allows for the direct religation of broken DNA ends without using template DNA as a guide (van Gent et al., 2001; Ferguson & Alt, 2001; Hoeijmakers, 2001; Venkitaraman, 2002; Schipler & Iliakis, 2013; Jeggo & Markus, 2015; Rode et al., 2016). In lieu of a template, NHEJ utilizes rapid repair kinetics to religate the broken ends before they have time to diffuse away from each other (Schipler & Iliakis, 2013), thus fitting two ‘sticky’ DNA ends back together (Danford, 2012). There is not, however, an inherent quality control check; as such, sections of DNA may be gained or lost, or the wrong ends may be rejoined (Schipler & Iliakis, 2013). There are two versions of this error-prone DNA repair: classical or canonical NHEJ (c-NHEJ), and alternative NHEJ (alt-NHEJ) (Schipler & Iliakis, 2013). It is not well understood when or why one pathway is selected over another (Venkitaraman, 2002; Schipler & Iliakis, 2013). It has been proposed that the phase of the cell cycle may influence repair pathway choice (Ferguson & Alt, 2001; Vodicka et al., 2018); for instance, HR is generally more common than NHEJ when sister chromatids are available in S and G2 phases of the cell cycle (Hoeijmakers, 2001; Venkitaraman, 2002). If both HR and c-NHEJ are compromised, alt-NHEJ, which is slower and more error-prone than c-NHEJ, is thought to be the stand-by repair mechanism (Schipler & Iliakis, 2013). 

If these repair processes are not able to properly and adequately repair the DNA, this may lead to the formation of chromosomal aberrations (CAs). CAs are defined as abnormalities in the chromosome structure, often due to losses or gains of chromosome sections or the entire chromosomes itself (van Gent et al., 2001; Durante & Cucinotta, 2008). These abnormalities can take many different forms and can be classified according to several different schemes. CAs can be defined as breaks, which occur when DSBs are not rejoined, or as exchanges, where the presence of multiple DSBs results in misrejoining of the DNA ends (Danford, 2012; Registre et al., 2016). CA classes can be further subdivided into chromosome-type aberrations (CSAs) that affect both sister chromatids, and chromatid-type aberrations (CTAs), affecting only one chromatid (Danford, 2012) . Examples of CSAs include chromosome-type breaks, centric ring chromosomes, and dicentric chromosomes (which have two centromeres), while CTAs refer to chromatid-type breaks and chromatid exchanges (Hagmar et al., 2004; Bonassi et al., 2008). Other types of CAs that may occur include micronuclei (MN; small nucleus-like structures containing chromosome fragments enclosed by a nuclear membrane (Fenech & Natarajan, 2011; Doherty et al., 2016)), nucleoplasmic bridges (NPBs; a stretch of chromatin enclosed by a nuclear membrane that is attached to two centromeres (Fenech & Natarajan, 2011; Russo et al., 2015)), nuclear buds (NBUDs; a MN that is still connected to the nucleus by nucleoplasmic material (Fenech & Natarajan, 2011)), and copy number variants (CNVs;  base pair to megabase pair deletions or duplications of chromosomal segments (Russo et al., 2015)). CAs may also be classified as stable aberrations (translocations, inversions, insertions and deletions) and unstable aberrations (dicentric chromosomes, acentric fragments, centric rings and MN) (Hunter & Muirhead, 2009; Qian et al., 2016). 

The strategy for collating the evidence to support the relationship is described in Kozbenko et al 2022.  Briefly, a scoping review methodology was used to prioritize studies based on a population, exposure, outcome, endpoint statement.

DNA repair is a modulating factor in this KER. The progression from “Inadequate DNA repair” to “Increase, Chromosomal aberrations” only occurs when "Increase, DNA strand breaks" (KE 1635) precedes "Inadequate DNA repair", which indicates that DNA strand breaks could not be repaired.   

Quantitative understanding of this linkage is lacking. Most data are derived from studies that examined DSB misrepair rates or CA rates in response to a radiation stressor.  In terms of inadequate DNA repair, the rate of DSB misrepair was found to be approximately 10 - 15% at 10 Gy of radiation (Lobrich et al. 2000); this rate increased to 50 - 60% at a radiation exposure of 80 Gy (Kuhne et al. 2000; Lobrich et al. 2000; Mcmahon et al. 2016). It is not known, however, how this rate of inadequate repair directly relates to CA frequency. Overall, more studies are required that directly assess this relationship.

This KER is plausible in all life stages, sexes, and organisms with chromosomes. The majority of the evidence is from in vitro fetal human male models. No in vivo evidence was found to support the relationship.