Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation

Abstract

The sensitivity of Xeroderma pigmentosa (XP) patients to sunlight has spurred the discovery and genetic and biochemical analysis of the eight XP gene products (XPA-XPG plus XPV) responsible for this disorder. These studies also have served to elucidate the nucleotide excision repair (NER) process, especially the critical role played by the XPA protein. More recent studies have shown that NER also involves numerous other proteins normally employed in DNA metabolism and cell cycle regulation. Central among these is ataxia telangiectasia and Rad3-related (ATR), a protein kinase involved in intracellular signaling in response to DNA damage, especially DNA damage-induced replicative stresses. This review summarizes recent findings on the interplay between ATR as a DNA damage signaling kinase and as a novel ligand for intrinsic cell death proteins to delay damage-induced apoptosis, and on ATR's regulation of XPA and the NER process for repair of UV-induced DNA adducts. ATR's regulatory role in the cytosolic-to-nuclear translocation of XPA will be discussed. In addition, recent findings elucidating a non-NER role for XPA in DNA metabolism and genome stabilization at ds-ssDNA junctions, as exemplified in prematurely aging progeroid cells, also will be reviewed.

Enzyme-free optical DNA mapping of the human genome using competitive binding

“…Regarding optical visualization of DNA damage sites, we foresee that the assay presented here could present diagnostic biomarkers for diseases linked to DNA-repair deficiencies, for example by locating damage sites in transcribed and non-transcribed regions of the genome (53,54). The approach could also allow for more fundamental studies on differences in damage loads across the genome when exposing cells to different damaging agents or hazardous environments.…”

RHOAming Through the Nucleotide Excision Repair Pathway as a Mechanism of Cellular Response Against the Effects of UV Radiation

“…Interestingly, XPA protein presents a distinct cell cycle-dependent localization, being retained at the cytosol in G1-phase, while it is mostly nuclear in G2-phase, independently of UV-damage. Under UV-stress, this protein translocates to the nucleus in S-phase through a ATR and p53 dependent mechanism, which is facilitated by importin-α4 in a process dependent on a unknown GTPase (Li et al, 2013;Musich et al, 2017). In other report, TGFβ leads to cell cycle arrest and inhibits proliferation through RhoA/ROCK pathway and induces nuclear localization of ERCC1/XPA and ERCC1/XPF complex (Bhowmick et al, 2003;Zheng et al, 2019).…”

“…ATR kinase is a primary key regulator of the NER pathway able to detect the DNA stress caused by UV-induced damage. During NER mechanism ATR, in complex with its nuclear binding partner ATR-interacting protein (ATRIP), binds to RPA-coated ssDNA generated by XPF/ERCC1 endonuclease complex and Exo1 activity, leading to the DDR signaling and cell cycle arrest through the Chk1 activation (Sertic et al, 2012;Musich et al, 2017). XPA protein accumulates in the nucleus after UV-exposure in a ATR-dependent manner, but not ATM (Wu et al, 2007), but, despite this information about DDR -NER mechanisms, many regulatory processes involved in the cellular responses are still unknown.…”

Focus on UV-Induced DNA Damage and Repair—Disease Relevance and Protective Strategies

“…Mutations in XPA have propounding effect on cellular physiology as the protein participates in both GG-NER and TC-NER. Moreover, defects in the XPA protein are responsible for the onset of Xeroderma pigmentosum (XP) with extreme sensitivity to UV radiation and higher predisposition to cancer [ 75 ]. Studies using XPA-deficient cells showed defects in ATR signaling upon DNA damage and suggest an additional role of XPA (to that observed in NER pathway) in damage signaling [ 73 ].…”