| Full text | |
| Author(s): |
Latancia, Marcela T.
;
Moreno, Natalia C.
;
Leandro, Giovana S.
;
Ribeiro, Victoria Chaves
;
de Souza, Izadora
;
Martins Vieira, William Kleber
;
Bastos, Andre Uchimura
;
Hoch, Nicolas Carlos
;
Rocha, Clarissa R. R.
;
Menck, Carlos F. M.
Total Authors: 10
|
| Document type: | Journal article |
| Source: | MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS; v. 878, p. 11-pg., 2022-05-18. |
| Abstract | |
Human DNA polymerases can bypass DNA lesions performing translesion synthesis (TLS), a mechanism of DNA damage tolerance. Tumor cells use this mechanism to survive lesions caused by specific chemotherapeutic agents, resulting in treatment relapse. Moreover, TLS polymerases are error-prone and, thus, can lead to mutagenesis, increasing the resistance potential of tumor cells. DNA polymerase eta (pol eta) - a key protein from this group - is responsible for protecting against sunlight-induced tumors. Xeroderma Pigmentosum Variant (XPV) patients are deficient in pol eta activity, which leads to symptoms related to higher sensitivity and increased incidence of skin cancer. Temozolomide (TMZ) is a chemotherapeutic agent used in glioblastoma and melanoma treatment. TMZ damages cells' genomes, but little is known about the role of TLS in TMZ-induced DNA lesions. This work investigates the effects of TMZ treatment in human XP-V cells, which lack pol eta, and in its complemented counterpart (XP-V comp). Interestingly, TMZ reduces the viability of XP-V cells compared to TLS proficient control cells. Furthermore, XP-V cells treated with TMZ presented increased phosphorylation of H2AX, forming gamma H2AX, compared to control cells. However, cell cycle assays indicate that XP-V cells treated with TMZ replicate damaged DNA and pass-through S-phase, arresting in the G2/M-phase. DNA fiber assay also fails to show any specific effect of TMZ-induced DNA damage blocking DNA elongation in pol eta deficient cells. These results show that pol eta plays a role in protecting human cells from TMZ-induced DNA damage, but this can be different from its canonical TLS mechanism. The new role opens novel therapeutic possibilities of using pol eta as a target to improve the efficacy of TMZ-based therapies against cancer. (AU) | |
| FAPESP's process: | 19/06039-2 - EMU awarded in the process 2018/18007-5: TissueFAXS microscope |
| Grantee: | Nicolas Carlos Hoch |
| Support Opportunities: | Multi-user Equipment Program |
| 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 |
| FAPESP's process: | 18/10061-0 - Role of translesion synthesis in cisplatin and temozolomide resistance in Glioma cells |
| Grantee: | Marcela Teatin Latancia |
| Support Opportunities: | Scholarships in Brazil - Doctorate |
| FAPESP's process: | 19/19435-3 - The role of DNA damage and mitochondrial function in vascular, immune and neurological ageing (DNA MoVINg) |
| Grantee: | Carlos Frederico Martins Menck |
| Support Opportunities: | Research Projects - Thematic Grants |