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The role of the yeast Shu complex in the error-free bypass of abasic sites and 3-Methylcytosines

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 (Unpublished)

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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
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Bonilla, Brauliobrauliobonilla@gmail.combrb1480000-0001-7468-9232
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairVan Houten, B.vanhoutenb@upmc.edu
Thesis AdvisorBernstein, K.A.karab@pitt.edu
Committee MemberYanowitz, J.L.yanowitzjl@mwri.magee.edu
Committee MemberRomero, G.G.ggr@pitt.edu
Committee MemberO'Sullivan, R.J.osullivanr@upmc.edu
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:
Date Deposited: 11 Jan 2021 15:28
Last Modified: 11 Jan 2021 15:28
URI: http://d-scholarship.pitt.edu/id/eprint/40136

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