Advanced search
Start date

Mechanisms of translesion synthesis in human cells

Grant number: 17/05680-0
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): June 01, 2017
Effective date (End): June 30, 2022
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Carlos Frederico Martins Menck
Grantee:Davi Jardim Martins
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:14/15982-6 - Consequences of repair deficiencies in damaged genome, AP.TEM


Ultraviolet (UV) light is a highly carcinogenic agent to which the human is exposed, that damages the cellular components and deforms the DNA strand and can result in cell death or gene instability. The lesions formed by UV light are usually removed by the Nucleotide Excision Repair mechanism (NER). When these lesions remain until the replication, there is a process known as translesion synthesis (TLS), a mechanism of tolerance to damage performed by specific polymerases. This mechanism allows the cell to continue replication and is partially under the control of the PCNA protein, which normally acts as a platform for DNA polymerases. There are two models proposed to explain how the TLS process occurs: directly after the replication fork blockage or by the gap-filling model. These tolerance mechanisms may occur through the action of one or more TLS polymerases (Pols). Among them, Pol eta (·) is the most studied and its absence leads to a milder phenotype of xeroderma pigmentosum (XP) syndrome, the variant form (XP-V). However, it is not yet known which TLS is involved in the tolerance of photoproducts in the absence of Pol·, leaving open an issue that touches directly on the explanation of mutagenesis in XP-V patients. It is known that Pol iota (¹), another Pol of TLS, is found together with Pol· in replication foci. In addition, we have recently found that Pol· induction is an important mechanism responsible for increasing cell survival of primary fibroblasts (NER deficient) after pre-treatment with low doses of UVC irradiation followed by irradiation at higher doses. However, this does not occur for primary fibroblasts deficient in Transcription Coupled Repair (TCR), perhaps due to structures formed after the transcription blockade by lesions, the R-loops. In this context, the objectives of the present project are to investigate the role of Pol¹ in the bypass of UV-induced photoproducts in repair-deficient human cells and to evaluate the effect of Pol· induction on TCR-deficient primary cells to understand how the induced replication has the TLS affected in this cells. For this, we will use cell lines silenced for Pol¹ and/or Pol· previously established in our laboratory, as well as primary fibroblasts from human patients with mutations in the XP-A and CSB genes. In addition, we also intend to characterize a cell line (from a patient with clinical phenotypes related to neurodegeneration) newly established in our laboratory with a new mutation in the gene encoding PCNA, investigating the consequence of this mutation on repair and tolerance processes of lesions in the genome. (AU)

News published in Agência FAPESP Newsletter about the scholarship:
Articles published in other media outlets (0 total):
More itemsLess items

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
MARTINS, DAVI J.; TIRMAN, STEPHANIE; QUINET, ANNABEL; MENCK, CARLOS F. M.. Detection of Post-Replicative Gaps Accumulation and Repair in Human Cells using the DNA Fiber Assay. JOVE-JOURNAL OF VISUALIZED EXPERIMENTS, v. N/A, n. 180, p. 14-pg., . (17/05680-0, 13/08028-1, 19/19435-3)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
MARTINS, Davi Jardim. Participation of DNA polymerase iota in the absence of Pol eta in translesion synthesis of human cells UV-irradiated and characterization of cells from patients mutated in PCNA. 2022. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) São Paulo.

Please report errors in scientific publications list using this form.