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 of maintaining 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.

Figure 1.

There are four different replication factor C (RFC) complexes. Each RFC is composed of four common subunits (Rfc2p, Rfc3p, Rfc4p, and Rfc5p) in addition to a specific subunit for each RFC. Rfc1p makes a general RFC complex with common subunits and function in general DNA replication for loading PCNA. Rad24p with common subunits functions specifically to load DNA damage checkpoint sensor Rad17p-Mec3p-Ddc1p to DNA damage. Ctf18p makes another RFC to unload PCNA where chromosome cohesion is established. The function of a RFC carrying Elg1p as a specific subunit is not clearly understood, yet.