6. La vida familiar
6.4 Algunos errores en la educación familiar
recently, we have shown that HLtf and sHPrH are functional homologs of yeast rad5. HLtf is fre- quently inactivated in colorectal and gastric cancers and sHPrH is frequently mutated in a wide variety of cancers. a requirement for HLtf and sHPrH in error-free postreplication repair of damaged dna is in keeping with their cancer-suppression role.
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Ildikó UNK / Principal Investigator, Group Leader
Andrea DARABA / staff scientist Miklós HALMAI / Phd. student vamsi KRISHNA / Phd student Szilvia MINORITS / technician
cancer is one of the major causes of death in the present world. The seemingly unrelated nature of its different types has made it very difficult to find a com- mon cause that can trigger it. However, a growing body of evidence supports the idea that the roots of cancers lie in mutations in dna, the genetic material of cells. dna damages caused by extrinsic or intrinsic agents are usually removed from dna and repaired by one of the several dna repair systems of the cell preserv- ing the genetic information. However, high exposure to dna damaging agents can lead to the accumulation of unrepaired dna damages that can block the replication machinery leading to cell death. to ensure survival, cells have evolved mechanisms that can sustain dna replica- tion on damaged dna. These so-called damage toler- ance or dna damage bypass processes allow replication to continue on damaged dna without removing the damaged bases. In humans, increased error-prone by- pass of dna lesions causes increased mutagenesis and a rise in the incidence of cancers, whereas error-free repli- cation of damaged dna contributes to genetic stability. In yeasts, the rad6-rad18 ubiquitin-conjugating complex governs three alternative pathways of rep- lication of uv-damaged dna: the rad5-dependent error-free, the dna polymerase η dependent error- free, and the dna polymerase ζ and rev1 dependent error-prone damage bypass.
The rad5-dependent pathway operates through a template switching mechanism, but specialized, so- called translesion synthesis dna polymerases work in the Polη and also in the Polζ and rev1 dependent pathways.
to activate any of the above three sub-pathways, first Pcna, the processivity factor of the replicative polymerase has to be ubiquitinated by rad6-rad18. monoubiquitination of Pcna activates the Polη and
Dna DamaGe ToleRanCe In eUkaRYoTes
(Dna RepaIR GRoUp)
Many factors participate in the regulation of peripheral immune tolerance and maintenance of the immune homeostasis by controlling the inflammatory and autoimmune processes in mammals. A powerful mechanism is the modulation of the pattern of cell surface glycosylation and the expression of soluble or cell-bound lectins inter- acting with their ligands. Among these lectins, galectin-1 is one of the master immunoregulators.
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Ildikó UNK
DNA DAMAGE TOLERANCE IN EUKARYOTES
the Polζ pathways, dependent on translesion synthesis polymerases. Polyubiquitination of that same residue of Pcna activates the rad5 pathway.
The most important questions about the rad6- rad18 dependent dna lesion bypass concern its regu- lation: How can ubiquitination of Pcna govern all three pathways? What are the downstream steps?
our main goal is to investigate the regulatory mechanisms of dna lesion bypass by rad6-rad18.
our hypothesis: to maintain the accurate duplica- tion of the genetic material, the access of low fidelity translesion synthesis dna polymerases, such as Polη and rev1, to the replication fork must be restricted to dna lesion sites. also, a mechanism should exist which provides preference to error-free lesion bypass pathways over the error-prone lesion bypass pathway. The regulation most probably involves specific protein interactions and posttranslational modifications, as strongly suggested by genetic data from yeast. Proteins
that interact with translesion synthesis polymerases are most probably involved in the regulation of dna damage bypass reactions.
We will identify proteins that mediate the rev1 de- pendent lesion bypass pathway and characterize these proteins by genetic and biochemical means. We will investigate whether the replicative polymerase Polδ is subject to posttranslational modification upon en- countering a dna lesion. also, we will examine the role of Pcna in mediating protein interactions neces- sary for activating the switch between the three sub- pathways. our results will provide insight into the mechanism of the regulation of lesion bypass path- ways and the polymerase exchange reactions between the replicative polymerase and translesion synthesis polymerases occurring at dna lesion sites.
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Éva MONOSTORI / Principal Investigator, Group Leader
Roberta FAJKA-BOJA / staff scientist ágnes CZIBULA / staff scientist Andrea BLASKó / Phd student Gábor J. SZEBENI / Phd student Julianna NOváK / Phd student Éva KRISTON-PáL / Phd student Lea vÉGH / Phd student
Andrea GERCSó / technician
lYmpHoCYTe sIGnal TRansDUCTIon laboRaToRY
Many factors participate in the regulation of peripheral immune tolerance and maintenance of the immune homeostasis by controlling the inflammatory and autoimmune processes in mammals. A powerful mechanism is the modulation of the pattern of cell surface glycosylation and the expression of soluble or cell-bound lectins inter- acting with their ligands. Among these lectins, galectin-1 is one of the master immunoregulators.