DNA repair and genomic instability in yeast aging

Aging is a universal process that occurs in eukaryotic organisms. Many features of aging, including the genetic pathways involved in aging, appear to be evolutionarily conserved. Extrachromosomal rDNA circles (ERCs) have been identified to be a cause of replicative aging in budding yeast S. cerevisiae. Genomic instability can cause ERCs to excise from chromosomal rDNA arrays, containing 35S and 5S rRNA genes. At each cell division, ERCs replicate via an origin of replication present in each rDNA repeat, accumulate asymmetrically in the mother cells due to their segregation bias, and ultimately cause nucleolar fragmentation and senescence. Introduction of an ERC into young cells shortens life span and accelerates the onset of age-associated sterility. ERCs are excised from the rDNA locus by homologous recombination. rad52 mutant cells, defective in DNA repair through homologous recombination, do not accumulate ERCs with age; likewise, mutations in other genes of the RAD52 class that have varying effects on homologous recombination have corresponding effects on ERC formation. rad52 mutation leads to a progressive delocalization of a silencing and DNA repair protein Sir3p from telomeres to other nuclear sites with age and, surprisingly, shortens life span despite the absence of ERCs. Spontaneous DNA damage, perhaps double-strand breaks (DSBs), are likely the cause of lethality in mutants of the RAD52 class and may be an initial step in aging in wild-type cells. Replication fork pausing in E. coli can cause DSBs. Consistently, afobl mutation, which abolishes unidirectional replication fork barrier (RFB) at the rDNA, reduces rDNA recombination, decreases ERC accumulation with age, and thus extends life span.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Biology.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2002

Author dc:creator

• Park, Peter Unnam, 1971-

Advisor dc:contributor.advisor

• Leonard Guarente.

• Biology.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/8389

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/8389