Functional analysis of somatic tumor mutations and rare polymorphisms of ATAD5

Authors

• SY Yoon
• KY Lee
• D Daee
• KJ Myung

Abstract

Proliferating Cell Nuclear Antigen (PCNA), which is a homotrimeric ring-structure complex plays an important role in coordinating the replication fork-associated process during the DNA damage response and replication process. The initial loading of PCNA on DNA to initiate each Okazaki fragment synthesis as well as whole replication process was catalyzed by the Replication factor C (RFC) complex. Unlike loading process of PCNA, unloading mechanism of PCNA was not clearly understood. Previously, we showed that ATAD5 protein, which is a mammalian homolog of yeast Elg1 protein, regulates the level of PCNA in chromatin during normal DNA replication as well as ubiquitylated PCNA in response to DNA damage. We also reported that haplo-insufficiency of ATAD5 in mice developed tumors and high incidences of somatic mutations of ATAD5 in human tumors. Collectively, we suggested that ATAD5 could be a novel tumor suppressor gene. To prove somatic mutations and SNPs of ATAD5 identified indeed affect the function of ATAD5 and promote tumorigenesis in human, we made 34 ATAD5 expression constructs with a mutation or SNP in ATAD5 that were collected from publically available databases and our studies. We found that clustered 5 variants lost their ability to interact with other RFC proteins suggesting the domain carrying these variants is important for making alternative RFC complex. We are currently investigating impact of these variants in regulation the level of PCNA in chromatin, the level of ubiquitylation of PCNA and other consequences in DNA metabolism including replication kinetics, recombination, and mutagenesis.

Scientific Focus Area: Cell Biology

This page was last updated on Friday, March 26, 2021