Function of TopBP1 in Genome Stability

Abstract

Human DNA topoisomerase IIbeta-binding protein 1 (TopBP1) and its orthologues in other organisms are proteins consisting of multiple BRCT modules that have acquired several functions during evolution. These proteins execute their tasks by interacting with a great variety of proteins involved in nuclear processes. TopBP1 is an essential protein that has numerous roles in the maintenance of the genomic integrity. In particular, it is required for the activation of ATM and Rad3-related (ATR), a vital regulator of DNA replication and replication stress response. The orthologues from yeast to human are involved in DNA replication and DNA damage response, while only proteins from higher eukaryotes are also involved in complex regulation of transcription, which is related to cell proliferation, damage response and apoptosis. We review here the recent progress in research aimed at elucidating the multiple cellular functions of TopBP1, focusing on metazoan systems.

Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress

“…The PCNA-like clamp 9-1-1 complex (Rad9-Rad1-Hus1) is recruited preferentially to the 5′-primed ssDNA/dsDNA junction by RPA and the clamp loader Rad17-RFC complex [102–105]. The ATR-ATRIP complex and 9-1-1 complexes are recruited to RPA-ssDNA independently and are bridged by the multiple-function protein TopBP1 (Topoisomerase IIβ binding protein 1) [106–110]. TopBP1 contains nine BRCT domains and is required for DNA replication initiation via the recruitment of CDC45 [111, 112].…”

TopBP1 in DNA Damage Response

“…Additionally, another repressor domain exists on the C terminus of the activation domain, which requires amino acids 586 -675. TopBP1 protein exerts its function in the nucleus and the carboxyl-terminal region of TopBP1 contains two putative nuclear localization signals (Going et al, 2007;Liu et al, 2003;Sokka et al, 2010). Liu et al (2003) showed that deletion of the BRCT7-8 and NLS region of TopBP1 induces cytoplasmic localization of the protein.…”

“…The process is catalyzed by the poly(ADP-ribose) polymerase (PARP) family of proteins. The best known of these proteins is PARP1 which is implicated in transcription, chromatin remodeling, apoptosis and DNA repair (Sokka et al, 2010;Woodhouse & Dainov, 2008). TopBP1 and PARP-1 interact both in vitro and in vivo.…”

“…Human TopBP1 recruits Cdc45 to origins of DNA replication and is required for the formation of the initiation complex of replication in human cells. The first, second and sixth BRCT domains of TopBP1 interact with Cdc45 and this interaction inhibits transcriptional activity of TopBP1 (Schmidt et al, 2008;Sokka et al, 2010). Both proteins interact exclusively at the G1/S boundary of cell cycle.…”

“…Mutations in this www.intechopen.com region have no effect on the basal activity of ATR, although they prevent ATR activation by TopBP1 protein and cause checkpoint defects and mimic a complete deletion of ATR in human somatic cells (Cimprich & Cortez, 2008;. Thus, efficient activation of ATR by TopBP1 protein may be required to achieve sufficient signal amplification for the proper execution of cellular response to DNA damage (Sokka et al, 2010). …”