Bonilla, Braulio
(2021)
The role of the yeast Shu complex in the error-free bypass of abasic sites and 3-Methylcytosines.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
This is the latest version of this item.
Abstract
Accurate DNA replication is critical to prevent genomic instability, which is a hallmark of cancer. Homologous recombination (HR) is responsible for error-free DNA damage bypass during replication. The yeast Shu complex is a recombination mediator primarily specialized in preventing replication-associated mutagenesis from endogenous DNA lesions as well as those from the alkylating agent methyl methanesulfonate (MMS). However, it remains unclear which are the specific DNA lesions that are tolerated by a Shu complex-mediated error-free pathway. To approach this problem, we performed a genome-wide sequencing of Shu complex disrupted cells chronically exposed to MMS. The analysis of the mutation pattern suggested abasic sites and 3-Methylcytosines as major contributors of mutagenesis in Shu complex deficient cells exposed to MMS. We, therefore, thought to validate these observations. In this work, we found that the Shu complex is enriched at the chromatin in cells that accumulate abasic sites and that it is important for the error-free bypass of APOBE3B-induced abasic sites. Moreover, we also showed that ectopic expression of the 3-Methylcytosine repair enzyme, ALKBH2, specifically rescues MMS-induced phenotypes seen in Shu complex mutant cells, such as growth defects and increased mutagenesis. Overall, our results demonstrate that yeast cells rely on a Shu complex-mediated error-free pathway to prevent mutagenesis from abasic sites and 3-Methylcytosines.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
11 January 2021 |
| Date Type: |
Publication |
| Defense Date: |
3 December 2020 |
| Approval Date: |
11 January 2021 |
| Submission Date: |
16 December 2020 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
133 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Molecular Pharmacology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Homologous recombination, Shu complex, DNA repair, mutagenesis, alkylation DNA damage, RAD51 paralogs, DNA replication |
| Related URLs: |
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| Date Deposited: |
11 Jan 2021 15:28 |
| Last Modified: |
11 Jan 2022 06:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/40136 |
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