Suppression of gross chromosomal rearrangements by a new alternative replication factor C complex

Abstract

Defects in DNA replication fidelity lead to genomic instability. Gross chromosomal rearrangement (GCR), a type of genomic instability, is highly enhanced by various initial mutations affecting DNA replication. Frequent observations of GCRs in many cancers strongly argue the importance to maintain high fidelity of DNA replication to suppress carcinogenesis. Recent genome wide screens in Saccharomyces cerevisiae identified a new GCR suppressor gene, ELG1, enhanced level of genome instability gene 1. Its physical interaction with proliferating cell nuclear antigen (PCNA) and complex formation with Rfc2-5p proteins suggest that Elg1 functions to load/unload PCNA onto DNA during a certain DNA metabolism. High level of DNA damage accumulation and enhanced phenotypes with mutations in genes involved in cell cycle checkpoints, homologous recombination (HR), or chromatin assembly in the elg1 strain suggest that Elg1p-Rfc2-5p functions in a fundamental DNA metabolism to suppress genomic instability. KeywordsGenomic instability; DNA replication; ELG1; RFC; PCNA DNA is constantly challenged by intracellular as well as environmental stress. Inaccurate repair of DNA damage by such stress can result in genomic instability that can manifest as gross chromosomal rearrangements (GCRs). GCRs include translocations, deletions, inversions, amplifications, chromosome end-to-end fusions, and aneuploidy [1]. These genetic malformations often lead to cell death or carcinogenesis. Frequent observations of genomic instability in tumor cells support the argument for the importance of proper DNA repair to suppress carcinogenesis.Multiple mutations in cancer normally exceed the expected number of mutations that cells are able to obtain with normal mutation rates. In order to generate multiple mutations, cells must develop specific initial mutations that can facilitate further mutagenesis [2]. These initial mutations, known as mutator mutations, have been suggested to facilitate multiple mutations in many oncogenes and tumor suppressor genes during carcinogenesis. Mutator mutations were first proposed from cases of the hereditary nonpolyposis colorectal cancer Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access A new member of RFC family (ELG1-RFC)Processing of stalled replication forks are usually modulated by a homo-trimeric DNA sliding clamp called PCNA in eukaryotes. Differential post-translational modifications in PCNA have been documented as a regulatory mechanism for many different DNA metabolisms including GCR [5]. Replication factor C (RFC) complex is a heteropentameric ...

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“…These phenotypes of the yeast elg1 mutant appeared to be caused by the increase of DNA damage during DNA replication and may indicate the same in human cells. ELG1 has a clear, but complex role in HR, which needs to be investigated further due to its complex role in multiple pathways affecting HR such as DNA replication, chromatin cohesion and DNA damage sensing 6–9,21,25–27…”

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