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Regulation and mechanism of replication of damaged DNA: role of yeast and human Rad5 and ubiquitylation

Objective

The stalling of DNA replication machinery that occurs as a consequence of encountering unrepaired DNA damage is a challenging problem for cells. In humans, increased error-prone bypass of DNA lesions causes increased mutagenesis, and as a consequence, a rise in the incidence of cancers, whereas error-free replication of damaged DNA contributes to genetic stability. In yeasts, the Rad6-Rad18 ubiquitin-conjugating complex governs three alternative pathways of replication of damaged DNA: the Rad5-dependent err or-free, the DNA polymerase eta dependent error-free, and the polymerase zeta dependent error-prone damage bypass. My research work has contributed to the great progress, which has been made in the past four years toward the understanding the function of translesion synthesis polymerases and unravelling how mutations in polymerase eta cause Xeroderma pigmentosum, a cancer prone syndrome.

However, it is still not known how the Rad5-dependent pathway stimulates error free replication of damaged DN A in yeasts, and whether a similar pathway in humans operates. How protein ubiquitylation governs damage bypass remains to be identified, as well. The goal of my proposed project is to answer these important questions. First, I propose to identify new protein elements in the yeast Rad5-pathway and to reconstitute it in vitro by highly purified protein factors. Second, I plan to examine human HLTF, a recently identified tumour suppressor, which can be the human homologue of yeast Rad5. I further propos e to unravel the role of protein ubiquitylation in giving access to Rad5 and translesion synthesis polymerases to the stalled replication machinery. My study will extend our understanding of the molecular events of DNA damage tolerance pathways, which prevents mutagenesis and carcinogenes.

Call for proposal

FP6-2004-MOBILITY-12
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Funding Scheme

IRG - Marie Curie actions-International re-integration grants

Coordinator

BIOLOGICAL RESEARCH CENTER OF THE HUNGARIAN ACADEMY OF SCIENCES
Address
Temesvari Krt. 62
Szeged
Hungary