ATR/Chk1 Pathway is Activated by Oxidative Stress in Response to UVA Light in Human Xeroderma Pigmentosum Variant Cells

Author(s)

Moreno, Natalia Cestari ^[1] ; Machado Garcia, Camila Carriao ^{[2, 3]} ; Reily Rocha, Clarissa Ribeiro ^[1] ; Munford, Veridiana ^[1] ; Martins Menck, Carlos Frederico ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Microbiol, Sao Paulo, SP - Brazil

^[2] Univ Fed Ouro Preto, NUPEB, Ouro Preto, MG - Brazil

^[3] Univ Fed Ouro Preto, Biol Sci Dept, Ouro Preto, MG - Brazil

• Document type: Journal article
• Source: Photochemistry and Photobiology; v. 95, n. 1, p. 345-354, JAN 2019.
• Web of Science Citations: 1

Abstract

The crucial role of DNA polymerase eta in protecting against sunlight-induced tumors is evidenced in Xeroderma Pigmentosum Variant (XP-V) patients, who carry mutations in this protein and present increased frequency of skin cancer. XP-V cellular phenotypes may be aggravated if proteins of DNA damage response (DDR) pathway are blocked, as widely demonstrated by experiments with UVC light and caffeine. However, little is known about the participation of DDR in XP-V cells exposed to UVA light, the wavelengths patients are mostly exposed. Here, we demonstrate the participation of ATR kinase in protecting XP-V cells after receiving low UVA doses using a specific inhibitor, with a remarkable increase in sensitivity and gamma H2AX signaling. Corroborating ATR participation in UVA-DDR, a significant increase in Chk1 protein phosphorylation, as well as S-phase cell cycle arrest, is also observed. Moreover, the participation of oxidative stress is supported by the antioxidant action of N-acetylcysteine (NAC), which significantly protects XP-V cells from UVA light, even in the presence of the ATR inhibitor. These findings indicate that the ATR/Chk1 pathway is activated to control UVA-induced oxidatively generated DNA damage and emphasizes the role of ATR kinase as a mediator of genomic stability in pol eta defective cells. (AU)

• FAPESP's process: 14/15982-6 - Consequences of repair deficiencies in damaged genome
• Grantee: Carlos Frederico Martins Menck
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 12/16929-6 - Effect of UVA light in cells from patients with variant Xeroderma pigmentosum
• Grantee: Natália Cestari Moreno
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center
• Grantee: Mayana Zatz
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC