Xeroderma Pigmentosum C: A Valuable Tool to Decipher the Signaling Pathways in Skin Cancers

Abstract

Xeroderma pigmentosum (XP) is a rare autosomal genodermatosis that manifests clinically with pronounced sensitivity to ultraviolet (UV) radiation and the high probability of the occurrence of different skin cancer types in XP patients. XP is mainly caused by mutations in XP-genes that are involved in the nucleotide excision repair (NER) pathway that functions in the removal of bulky DNA adducts. Besides, the aggregation of DNA lesions is a life-threatening event that might be a key for developing various mutations facilitating cancer appearance. One of the key players of NER is XPC that senses helical distortions found in damaged DNA. The majority of XPC gene mutations are nonsense, and some are missense leading either to the loss of XPC protein or to the expression of a truncated nonfunctional version. Given that no cure is yet available, XPC patients should be completely protected and isolated from all types of UV radiations (UVR). Although it is still poorly understood, the characterization of the proteomic signature of an XPC mutant is essential to identify mediators that could be targeted to prevent cancer development in XPC patients. Unraveling this proteomic signature is fundamental to decipher the signaling pathways affected by the loss of XPC expression following exposure to UVB radiation. In this review, we will focus on the signaling pathways disrupted in skin cancer, pathways modulating NER’s function, including XPC, to disclose signaling pathways associated with XPC loss and skin cancer occurrence.

Generation and characterization of CRISPR-Cas9-MediatedXPCGene Knockout in Human Skin Cells

“…Research articles investigating the link between XPC, and skin biology concentrate on primary XPC-mutated keratinocytes and fibroblasts 17,18 . As previously highlighted, the absence of an appropriate control in primary XP-C cells hinders the comparison of outcome data, posing a challenge in exploring the molecular events associated with this disease, especially given the inherent heterogeneity among individuals and we should be aware that since the GG-NER DNA repair system is absent in XP-C patients, a higher susceptibility to other unknown genetic mutations can occur hindering the precise outcomes 7 . Therefore, the utilization of CRISPR-Cas9 would be advantageous, providing a significant benefit by generating a mirrored control and facilitating precise outcome results that are specifically related to the loss of XPC.…”

“…This involves enlisting the XPD and XPB helicase components from the TFIIH complex to uncoil the DNA in the vicinity of the damaged site. Once XPA has confirmed the damage, the nucleases XPF and XPG remove the damaged displaced strand, resulting in a gap that is filled and sealed by the DNA polymerase and ligase machinery 7 .…”

“…This involves enlisting the XPD and XPB helicase components from the TFIIH complex to uncoil the DNA in the vicinity of the damaged site. Once XPA has confirmed the damage, the nucleases XPF and XPG remove the damaged displaced strand, resulting in a gap that is filled and sealed by the DNA polymerase and ligase machinery 7 . Deficiencies in NER are linked to various disorders, including Xeroderma pigmentosum (XP), Cockayne syndrome (CS), Trichothiodystrophy (TTD), Cerebro-oculo-facio-skeletal syndrome (COFS), UV-sensitive syndrome (UVsS), and combined phenotypes, e.g.…”