Xeroderma pigmentosum (XP), a rare autosomal recessive genetic disorder, is characterized by injury due to solar radiation to the exposed surfaces of the body namely, the skin and ocular surface. The reported global incidence of the disease ranges between 1 per million births to 45 per million births with higher prevalence in cultures promoting consanguineous marriages (Hirai et al., 2006; Kleijer et al., 2008; Kraemer and Slor, 1985; Messaoud et al., 2010; Soufir et al., 2010). Ocular signs vary from photo-keratitis, pterygium, corneal haze, droplet keratopathy, corneal vascularization, and dryness to cancerous lesions on the ocular surface (Brooks et al., 2013; Chaurasia et al., 2014; Goyal et al., 1994; Kaliki et al., 2019; Kraemer et al., 1987; Nandyala et al., 2021; Rezaei Kanavi et al., 2008; Yam and Kwok, 2014).

The cornea absorbs different wavelengths of UV radiations ranging from 240 to 400 nm (UV-A and UV-B) (Kolozsvari et al., 2002). It is well known that the maximum UV absorption and DNA damage is encountered by the epithelial cells (Mallet and Rochette, 2013) and excessive damage can lead to photo-keratitis and transient corneal haze (Podskochy, 2004; Podskochy et al., 2000). These cells are capable of regeneration and the damaged cells can be replaced in addition to being repaired. Though only about 20% of the incident UV penetrates the inner layers of the cornea, cellular changes and cell death have been reported in the endothelial cells following exposure (Ringvold et al., 1982). Several studies have reported a reduction in corneal endothelial density in patients with XP compared to age matched controls indicating that low penetrance of UV in these eyes is sufficient to cause DNA damage in these cells due to defective DNA repair. Histopathological analyses of XP corneas shows thickening of the Descemet's membrane confirming the presence of damage in the deeper layers of the cornea (Aghaei et al., 2020; Chaurasia et al., 2014; Karai et al., 1984; Mohamed et al., 2016; Okubo et al., 1987).

Damage to the DNA occurs when UV is absorbed leading to the formation of cyclobutane pyrimidine dimers (CPDs) and 6-4 pyrimidine-pyrimidone photoproducts. To repair these photoproducts, the NER (Nucleotide Excision Repair) pathway, made up of several proteins, is activated. These proteins are coded for by genes labelled XPA-XPG and XPV(Costa et al., 2003). While XPA, XPC and XPE are involved in sensing the DNA damage, XPB and XPD are required for DNA strand opening around the damaged bases. Endonucleases XPG and XPF incise to release the damaged strand so that DNA can be resynthesized by the respective polymerases. XPV is not involved directly in the NER pathway but codes for DNA polymerase ƞ (PolH) that ensures continued DNA replication downstream of damage site. Though mutations have been reported in all the genes involved in the repair pathway, XPA (25%), XPC (25%), POLH1 (21%), and XPD (15%) are the most frequently affected (Martens et al., 2021).

Normal cells actively detect and repair DNA damage, preserving DNA integrity with minimal impact. However, an accumulation of unrepaired DNA activates damage response proteins (DDR), namely ATR (Ataxia telangiectasia and Rad3-related protein) and ATM (Ataxia-Telangiectasia mutated), which halt cell cycle progression until DNA repair occurs. Direct interaction between components of the NER and DDR pathway has been demonstrated before suggesting that these pathways work together to safeguard DNA strand integrity thereby preventing mutation accumulation or propagation (Shell et al., 2009). In cases of excessive damage, cells cease repair and trigger apoptosis, with p53 playing a central role.

Previous studies have significantly contributed to understanding the clinical and histopathological changes in the corneas in XP patients (Chaurasia, 2018; Chaurasia et al., 2014; Nandyala et al., 2021; Rezaei Kanavi et al., 2008). Few studies have demonstrated UV-induced DNA damage/repair in ocular cells mainly using animal corneas or cultured cells (De Vries et al., 1998; Estil et al., 1997; Inoki et al., 2004; Mallet et al., 2016; Mallet and Rochette, 2011; Podskochy et al., 2000; Ringvold et al., 1982). Our goal in this study was to provide evidence for the presence of persistent DNA damage in the corneal cells of XP patients.